USPTO Patents Application 09993647

(19)

Europaisches Patentamt
European Patent Office
Office europeen des brevets

EP 1 199 306 A1

(12)

EUROPEAN PATENT APPLICATION

published in accordance with Art. 158(3) EPC

(51) int ci 7; C07D 213/75, C07D 213/81,

C07D 239/42, C07D 239/47,
C07D 241/20, C07D 241/40,
C07D 277/48, C07D 277/82,
C07D 487/04, C07D 519/00,
C07D 498/04, C07D 409/12,
C07D 417/12, C07D 401/10,
A61 K 31/4402, A61 K 31/44,
A61 K 31/4439, A61 K 31/505,
A61K 31/50, A61K 31/415,
A61K 31/426

(86) International application number:
PCT/JP00/04991

(87) International publication number:

WO 01/07411 (01.02.2001 Gazette 2001/05)

(84)

Designated Contracting States:

•

HAYASHI, Kyoko,

AT BE CH CY DE DK ES Fl FR GB GR IE IT LI LU

Banyu Pharmaceutical Co. Ltd.

MC NL PT SE

Ibaraki 300-2611 (JP)

Designated Extension States:

•

HONMA, Teruki, Banyu Pharmaceutical Co. Ltd.

AL LT LV MK RO SI

Ibaraki 300-2611 (JP)

•

TAKAHASHI, Ikuko,

(30)

Priority: 26.07.1999 JP 21138499

Banyu Pharmaceutical Co. Ltd.

Ibaraki 300-2611 (JP)

(71)

Applicant: BANYU PHARMACEUTICAL CO., LTD.

Chuo-ku, Tokyo 103-8416 (J P)

(74)

Representative: Teipel, Stephan et al

Lederer & Keller

(72)

Inventors:

Patentanwalte

•

HAY AM A, Takashi,

Prinzregentenstrasse 16

Banyu Pharmaceutical Co. Ltd.

80538 Munchen (DE)

Tsukuba-shi, Ibaraki 300-2611 (JP)

(54) BIARYLUREA DERIVATIVES

(43) Date of publication:

24.04.2002 Bu lletin 2002/1 7

(21) Application number: 00949909.6

(22) Date of filing: 26.07.2000

(57) The present invention relates to a compound of
Formula (I) and the manufacturing method(s) thereof
and the use thereof:

Formula ( I )

<

CO

o

CO

<J>

(0

,wherein: Ar is a nitrogen-containing hetero aromatic
ring group; X and Z are each a carbon atom, and so on ;
Y is CO, and so on; R 1 is a hydrogen atom, and so on;
R 2 and R 3 are each a hydrogen atom, and so on; R 4 and
R 5 are each a hydrogen atom, and so on; and the for-
mula ™ is a single bond or a double bond.

According to the present invention, the compound
of the present invention can provide Cdk4 and/or Cdk6
inhibitors for treating malignant tumors, because the
compounds of the present invention exhibit a prominent
growth inhibitory activity against tumor cells.

Q.

LU

Printed by Jouve ; 75001 PARIS (FR)

EP 1 199 306 A1

Description
Technical Field

5 [0001] The present invention relates to biarylurea derivatives di -substituted with aromatic ring or heteroaromatic ring,
which are useful as pharmaceutical composition, and to the production method and use thereof.

Background Art

10 [0002] In the growth of the normal cells, cell division and its pause occur orderly according to the cell cycle, on the
contrary, the growth of cancer cells is characterized by its disorderedness, thus the abnormality in the cell-cycle reg-
ulating system is presumed to be directly related to the oncogenesis and maligunant degeneration of cancer. The cell
cycle of mammalian cells is controlled by a group of serine/threonine kinase called as cyclin dependent kinase (here-
inafter denoted as "Cdk") family. Cdk needs to form a complex with a regulatory subunit called cyclin, in order to exhibit

*s its enzyme activity. Cyclins also have a family. Each Cdk molecule of which is considered to regulate progression at a
specific stage of the cell cycle by forming a complex with the specific cyclin molecule which is expressed at the corre-
sponding stage of the cell cycle. For example. D-type cyclin regulates the progression of G1 phase by binding to Cdk4
or Cdk6, and cyclin E-Cdk2 regulates the progression of G1/S boundary, cyclin A-Cdk2 regulates the progression of
S stage, and furthermore, cyclin B-cdc2 regulates the progression of G2/M, respectively. In addition, there are three

20 subtypes D1 , D2 and D3 in D type cyclin. Furthermore, Cdk activity is considered to be regulated not only by the binding
with cyclins, but also by phosphorylation/dephosphorylation of Cdk molecule, degradation of the cyclin molecule and
binding with Cdk-inhibitor proteins. [Advances in Cancer Research (Advance Cancer Res.), Vol.66, pp. 1 81-212(1 995);
Current Opinion in Cell Biology (Current Opin. Cell Biol.), Vol.7, pp. 773-780 (1995); Nature (Nature), Vol. 374, pp.
131-134 (1995)].

25 [0003] The Cdk-inhibitor proteins of mammalian cells can be divided broadly into two categories, Cip/Kip family and
INK4 family according to their structures and properties. The former inhibits a variety of cyclin-Cdk complexes broadly,
whereas the latter inhibits Cdk4 and Cdk6 specifically [Nature (Nature), Vol.366, pp. 704-707 (1993); Molecular and
Cellular Biology (Mol. Cell. Biol.), Vol. 15, pp. 2627-2681 (1995); Genes and Development (Genes Dev.), Vol. 9, pp.
1149-1163 (1995)].

30 [0004] Cip/Kip family can be represented by p21 (Sdil/Cip1/Waf1), and its expression induced by the tumor suppres-
sor gene product p53 [Genes and Development (Genes Dev.), Vol.9, pp. 935-944 (1995)]

[0005] On the other hand, p16 (INK4a/MTS1/CDK4l/CDKN2), for example, is one of the Cdk inhibitor proteins which
belong to INK family. Human p1 6 gene is encoded on the chromosome 9p21 . Abnormalities of this locus are detected
with a high frequency in human cancer cells. Actually, a lot of cases of deletion and mutation of the p16 gene have
35 been reported. Also, a high frequency of tumorigenesis in the p1 6 knockout mice has been reported [Nature Genetics
(Nature Genet.), Vol. 8, pp. 27-32 (1 994); Trends in Genetics (Trends Genet.), Vol. 11, pp. 136-140 (1995); Cell (Cell),
Vol. 85, pp. 27-37 (1996)].

[0006] Each Cdk regulates the progression of cell cycle by phosphorylating the target protein at the specific phase
of cell cycle, and retinoblastoma (RB) protein is considered to be one of the most important target proteins. RB protein

40 is the key protein that regulates the progression from G1 phase to S phase. It is phosphorylated rapidly in the period
from late G1 phase through early S phase. The phosphorylation is considered to be carried out by the cyclin
D-Cdk4/Cdk6 complex, followed by the cyclin E-Cdk2 complex, leading the progression of cell cycle. The complex
composed of hypophosphorylated RB and transcription factor E2F at dissociates when RB protein becomes hyper-
phosphorylated. As a result, E2F will become the transcriptional activator, and at the same time, the suppression of

45 the promoter activity due to the RB-E2F complex will be removed, thus leading to the activation of the E2F-dependent
transcription. At present, the Cdk-RB pathway, which consists of E2F and its suppressor RB protein, Cdk4/Cdk6 which
repressively regulates the function of RB protein, Cdk inhibitor protein which controls the kinase activity of Cdk4/Cdk6,
and D-type cyclin is thought to be the important mechanism to regulate the progression of G1 phase to S phase [Cell
(Cell), Vol. 58, pp. 1097-1105 (1989); Cell (Cell), Vol. 65, 1053-1061 (1991); Oncogene (Oncogene), Vol. 7, pp.

50 1067-1074 (1992); Current Opinion in Cell Biology (Curren Opin. Cell Biol.), Vol. 8, pp. 805-81 4 (1 996); Molecular and
Cellular Biology (Mol. Cell. Biol.) ; Vol. 18 ; pp. 753-761 (1998)].

[0007] In fact, the DNA binding sequence of E2F is, for example, in the promoter region of many genes related to
cell proliferation and are important during S phase. The transcription of more than one of them has been reported to
be activated in an E2F-dependent manner during the period from late G1 phase to early S phase [The EMBO Journal
55 (EMBO J.), Vol. 9, pp.21 79-21 84 (1990); Molecular and Cellular Biology (Mol. Cell. Biol), Vol. 13, pp. 1610-1618(1993)].
[0008] Abnormalities of any factors composing Cdk-RB pathway such as deletion of functional p1 6, high expressions
of cyclin D1 and Cdk4, and deletion of functional RB protein have been detected with a high frequency in human
cancers [Science (Science), Vol. 254, pp. 1138-1146 (1991); Cancer Research (Cancer Res.), Vol. 53, pp. 5535-5541

2

EP 1 199 306 A1

(1993); Current Opinion in Cell Biology (Current Opin. Cell Biol.), Vol. 8, pp. 805-814 (1996)]. As all of them lead to
abnormalities of promoting the progression from G1 to S phase, it is clear that this pathway plays a crucial role in
tumorigenesis of cells or the neoplasia of cancer cells.

[0009] As for the known compounds having Cdk family inhibitory activity, a series of chromone derivatives repre-
5 sented by, for example, flavopiridol. (W097/16447, 98/13344) are already known.

[0010] As the prior art structurally similar to the compounds of the present invention, there may be cited, for example,
W096/25157 (reference A), W097/29743 (reference B), US-patent 56961 38 (reference C) and Japanese Patent Pub-
lication for Laid-Open 115176/1989 (reference D).

[0011] References A and B disclose ureas or thioureas derivatives, both of which are substituted with the aryl groups
10 on both N- and N'-positions. But, the aryl groups in the references A and B are completely different from nitrogen-
containing heteroaromatic ring groups of the present invention in view of the chemical structure, thus it can be safely
said that the compounds disclosed in the references A and B have no direct relationship with the compounds of the
present invention. Furthermore, the use of the compounds disclosed in the references A and B is related to chemokine
receptor antagonists, intended for producing a therapeutic agent for treating, for example, psoriasis, atopic dermatitis,
15 asthma, chronic occlusive pulmonary disease and Alzheimer's disease, and so on, thus, having no relationship with
the use of compounds of the present invention.

[0012] In the reference C, urea orthiourea derivatives are disclosed, having aromatic cyclic groups which may contain
one nitrogen atom and benzene rings which may be condensed. The main compounds of the invention in the reference
C are, however, urea derivatives substituted with two phenyl groups on the N- and N'-positions, and three urea deriv-

20 atives substituted with a pyridyl group on the N'-position are disclosed only in the third column (on lines 11,13 and
26), in the fifth column (on lines 17 and 19), in the seventh column (on lines 13 and 15), in the seventeenth column
(on lines 24 and 42) and in the twentieth column (on the 14th line from the bottom of the column) of the specification.
Descriptions in these columns are common. In addition, all the substituents, which exsist on the N-position of the urea
compounds, are phenyl groups, thus the compounds are completely different from those of the present invention.

25 Furthermore, in the case where the compounds of the reference C may have a fused benzene ring as the N-substituent,
although it is defined that the ring structures which are fused with the benzene ring may be saturated or unsaturated,
there is no description about the substituents on the fused ring, thus, said fused ring is interpreted to be non-substituted
on the fused ring (in contrast, the compounds of the present invention have an oxo-group there). And, in addition,
judging from the description in the reference C, the examples of the fused benzene ring are limited to naphthyl groups.

30 Thus, the compounds in the reference C and those in the present invention differ in their chemical structures, and it
can be said that the two inventions have no direct relationship with each other.

[0013] Furthermore, the use of the compounds described in the reference C is related to the potassium channel
activators, as described in the sixteenth column, aiming at a therapeutic agent for treating, for example, potassium
channel dependent convulsion, asthma, ischemia, and so on, so there is no relations of it with the use of the present
35 invention.

[0014] In the Example 7 in the reference D, a urea compound wherein the N-position is substituted with a triazinyl
group and the N'-position is substituted with a 9-fluorenone group.

[0015] The invention of the reference D is the one which relates to radiosensitive compositions, namely, photosen-
sitive agents, and differs from the present invention in term of the technical fields they belong to, and also no other

40 compound similar to the compound of the present invention is mentioned, except for that in the Example 7 described
above. Because the compounds in the reference D are the compounds having various types of structure, that is, a
triazine nucleus is used as the core structure, more than ten substituents containing a fluorenone group are applied
at a photo-initiation part of the triazine nucleus, and more than ten combinations of connecting groups including urea,
which connect a photo-initiation part and a triazine nucleus, are exemplified. Therefore, it is safely stated that the

45 compounds of the present invention and the use thereof cannot be reached from the descriptions in the reference D
including the compound in the Example 7, and the reference D is an invention which has no direct relation to the present
invention.

[0016] Thus, since the present invention relates to the novel compounds which have not been described in the
literatures yet and the novel use thereof, also the present invention can not be attained easily based on the above-
50 mentnioned reference A to D.

[0017] Furthermore, up to date, no Cdk6 inhibitor is exemplified.

[0018] As stated above, some chromone derivatives can be exemplified as the compounds with Cdk family inhibitory
activity, however, their inhibitory activity against Cdk4 is not strong enough, and compounds with a higher activity are
still desired. More specifically, novel compounds which will simultaneously show heterogenous inhibitory activities, for
55 example, against Cdk6 and so on, different from the known inhibitors, are desired.

3

EP 1 199 306 A1

Disclosure of the Invention

[0019] The present inventors have assiduously studied so as to provide novel compounds having an excellent Cdk4-
or Cdk6- inhibitory activity, and as a result, found that a series of novel compounds having biarylurea structure show
Cdk4- and/or Cdk6-inhibitory activity, and thus completed the present invention.

[0020] The present invention relates to a compound represented by Formula (I) or pharmaceutical^ acceptable salts
thereof, preparation methods thereof and the use thereof:

, wherein: Ar is a nitrogen-containing heteroaromatic ring group selected from a set of groups of a pyridyl group, a
pyrimidinyl group, a pyradinyl group, a pyridazinyl group, a thiazolyl group, an isothiazolyl group, an oxazolyl group,
an isoxazolyl group, a pyrazolyl group, a pyrrolyl group, an imidazolyl group, an indolyl group, an isoindolyl group, a
quinolyl group, an isoquinolyl group, a benzothiazolyl group, and a benzoxazolyl group, which:

(1 ) may be substituted with one to three of the same or different substituent(s) selected from either a set of groups
consisting of a lower alkyl group, a hydroxyl group, a cyano group, halogen atoms, a nitro group, a carboxyl group,
a carbamoyl group, aformyl group, a lower alkanoyl group, a lower alkanoyloxy group, a hydroxy lower alkyl group,
a cyano lower alkyl group, a halo lower alkyl group, a carboxy lower alkyl group, a carbamoyl lower alkyl group,
lower alkoxy group, a lower alkoxycarbonyl group, lower alkoxycarbonylamino group, a lower alkoxycarbonylamino
lower alkyl group, a lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group, a carbamoyloxy group, a lower
alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, an amino group, a lower alkylamino group, a di-lower
alkylamino group, atri-lower alkylammonio group, an amino lower alkyl group, a lower alkylamino lower alkyl group,
a di-lower alkylamino lower alkyl group, a tri-lower alkylammonio lower alkyl group, a lower alkanoylamino group,
an aroylamino group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl
group, a lower alkylsulfonylamino group, a hydroxyimino group and a lower alkoxyimino group, or a set of groups
represented by a formula V 1 -W 1 -Y 2 -R p (wherein: R p is any of a hydrogen atom, or a lower alkyl group, a lower
alkenyl group or a lower alkynyl group which may be substituted with one to three of said substituent(s), or a cyclo
lower alkyl group, an aryl group, a heteroaromatic ring group selected from a set of groups consisting of an imi-
dazolyl group, an isoxazolyl group, an isoquinolyl group, an isoindolyl group, an indazolyl group, an indolyl group,
an indolizinyl group, an isothiazolyl group, an ethylenedioxyphenyl group, an oxazolyl group, a pyridyl group, a
pyradinyl group, a pyrimidinyl group, a pyridazinyl group, a pyrazolyl group, a quinoxalinyl group, a quinolyl group,
a dihydroisoindolyl group, a dihydroindolyl group, a thionaphthenyl group, a naphthyridinyl group, a phenazinyl
group, a benzoimidazolyl group, a benzoxazolyl group, a benzothiazolyl group, a benzotriazolyl group, a benzo-
furanyl group, a thiazolyl group, a thiadiazolyl group, a thienyl group, a pyrrolyl group, a furyl group, a furazanyl
group, a triazolyl group, a benzodioxanyl group and a methylenedioxyphenyl group, or an aliphatic heterocyclic
group selected from a set of groups of an isoxazolinyl group, an isoxazolidinyl group, a tetrahydropyridyl group,
an imidazolidinyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a piperazinyl group, a piperidinyl
group, a pyrrolidinyl group, pyrrolinyl group, a morpholino group, a tetrahydroquinolinyl group and a tetrahydroi-
soquinolinyl group, each of which cyclic group may be substituted with one to three of said substituent(s) or, fur-
thermore, may have a bicyclic or tricyclic fused ring of a partial structure selected from a set of groups consisting of:

Formula ( I )

5

o . O - £)

EP 1 199 306 A1

; W-, is asinglebond, an oxygen atom, a sulfur atom, SO, S0 2 , NR q , S0 2 NR q , N(R q )S0 2 NR r , N(R q )S0 2 , CH(OR q ),
CONR q , N(R q )CO, N(R q )CONR r , N(R q )COO ; N(R q )CSO, N(R q )COS, C(R q )=CR p C=C, CO, CS, OC(O), OC(O)
NR q , OC(S)NR q , SC(O), SC(0)NR q and C(0)0 (wherein: R q and R r are respectively a substituent selected from
a set of groups of (i) a hydrogen atom, (ii) a substituent selected from a set of groups consisting of a lower alkyl
group, a cyclo lower alkyl group, a hydroxyl group, a cyano group, halogen atoms, a nitro group, a carboxyl group,
a carbamoyl group, aformyl group, a lower alkanoyl group, a lower alkanoyloxy group, a hydroxy lower alkyl group,
a cyano lower alkyl group, a halo lower alkyl group, a carboxy lower alkyl group, a carbamoyl lower alkyl group,
lower alkoxy group, a lower alkoxycarbonyl group, lower alkoxycarbonylamino group, a lower alkoxycarbonylamino
lower alkyl group, a lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group, a carbamoyloxy group, a lower
alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, an amino group, a lower alkylamino group, a di-lower
alkylamino group, atri-lower alkylammonio group, an amino lower alkyl group, a lower alkylamino lower alkyl group,
a di-lower alkylamino lower alkyl group, a tri-lower alkylammonio lower alkyl group, a lower alkanoylamino group,
an aroylamino group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl
group, a lower alkylsulfonylamino group, a hydroxyimino group and a lower alkoxyimino group, or (iii) a lower alkyl
group, an aryl group or an aralkyl group which may be substituted with one to three of said substituent(s).); Y-| and
Y 2 are each, the same or different, a single bond or a straight-chain or branched lower alkylene group which may
have a said bicyclic or tricyclic fused ring);

(2) may have a five- to seven-membered fused ring selected from a set of groups consisting of:

which may be formed together with the carbon atom of said nitrogen-containing heteroaromatic ring group, on
which the substituent, which is selected from a set of groups consisting of a lower alkyl group, a lower alkanoyl
group, a lower alkanoyloxy group, a hydroxy lower alkyl group, a cyano lower alkyl group, a halo lower alkyl group,
a carboxy lower alkyl group, a carbamoyl lower alkyl group, lower alkoxy group, a lower alkoxycarbonyl group,
lower alkoxycarbonylamino group, a lower alkoxycarbonylamino lower alkyl group, a lower alkylcarbamoyl group,
a di-lower alkylcarbamoyl group, a carbamoyloxy group, a lower alkylcarbamoyloxy group, di-lower alkylcarbamoy-
loxy group, an amino group, a lower alkylamino group, a di-lower alkylamino group, atri-lower alkylammonio group,
an amino lower alkyl group, a lower alkylamino lower alkyl group, a di-lower alkylamino lower alkyl group, a tri-
lower alkylammonio lower alkyl group, a lower alkanoylamino group, an aroylamino group, a lower alkylsulfinyl
group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, and a lower alkanoylamidino lower alkyl group
(hereinafter indicated as ring-substituent) stands, the carbon atom next to said carbon atom, and a carbon atom,
an oxygen atom and/or a nitrogen atom on said ring-substituent; or,
(3) may have a five- to seven-membered ring selected from a set of groups consisting of:

which may be formed together with the carbon atom of said nitrogen-containing heteroaromatic ring group on

EP 1 199 306 A1

which asubstituent represented by the formula Yi-Wi-Y 2 -R p (wherein: Y-j, W-j, Y 2 and R p have the same meanings
as stated above) stands, the carbon atom next to said carbon atom, and a carbon atom, an oxygen atom and/or
a nitrogen atom on said ring-substituent.

; X and Z are each, the same or different, a carbon atom or a nitrogen atom, or being taken together with R 1 or R 2

5 and/or R 3 which may exist on X or Z, form a CH or a nitrogen atom; Y is CO, SO or S0 2 ; R-| is any of a hydrogen

atom or a substituent represented by a formula Y 3 -W2-Y 4 -R s (wherein: R s is any of a hydrogen atom or a lower
alkyl group, a lower alkenyl group, a lower alkynyl group, a cyclo lower alkyl group, an aryl group, and a heteroar-
omatic ring group selected from a set of groups consisting of an imidazolyl group, an isoxazolyl group, an isoquinolyl
group, an isoindolyl group, an indazolyl group, an indolyl group, an indolizinyl group, an isothiazolyl group, an

10 ethylenedioxyphenyl group, an oxazolyl group, a pyridyl group, a pyradinyl group, a pyrimidinyl group, a pyridazinyl

group, a pyrazolyl group, a quinoxalinyl group, a quinolyl group, a dihydroisoindolyl group, a dihydroindolyl group,
a thionaphthenyl group, a naphthyridinyl group, a phenazinyl group, a benzoimidazolyl group, a benzoxazolyl
group, a benzothiazolyl group, a benzotriazolyl group, a benzofuranyl group, athiazolyl group, athiadiazolyl group,
a thienyl group, a pyrrolyl group, a furyl group, a furazanyl group, a triazolyl group, a benzodioxanyl group and a

15 methylenedioxyphenyl group, or an aliphatic heterocyclic group selected from a set of groups comprising an iso-

xazolinyl group, an isoxazolidinyl group, a tetrahydropyridyl group, an imidazolidinyl group, a tetrahydrofuranyl
group, a piperazinyl group, a piperidinyl group, a pyrrolidinyl group, pyrrolinyl group, a morpholino group, a tet-
rahydroquinolinyl group and a tetrahydroisoquinolinyl group, all of which may be substituted with one to three of
said substituent(s); W 2 is a single bond, an oxygen atom, a sulfur atom, SO, S0 2 , NR t , S0 2 NR t , N(R t )S0 2 NR u , N

20 (R t )S0 2 , CH(OR t ), CONR t , N(R t )CO, N(R t )CONR u , N(R t )COO, N(R t )CSO, N(R t )COS, C(R v )=CR r , C=C, CO, CS,

OC(O), OC(0)NR t , OC(S)NR t , SC(O), SC(0)NR t and C(0)0 (wherein: R t and R u are each a hydrogen atom or a
substituent selected from a set of groups consisting of a lower alkyl group, a hydroxy group, acyano group, halogen
atoms, a nitro group, a carboxyl group, a carbamoyl group, a formyl group, a lower alkanoyl group, a lower al-
kanoyloxy group, a hydroxy lower alkyl group, a cyano lower alkyl group, a halo lower alkyl group, a carboxy lower

25 alkyl group, a carbamoyl lower alkyl group, lower alkoxy group, a lower alkoxycarbonyl group, a lower alkoxycar-

bonylamino group, a lower alkoxycarbonylamino lower alkyl group, a lower alkylcarbamoyl group, a di-lower alkyl-
carbamoyl group, a carbamoyloxy group, a lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, an
amino group, a lower alkylamino group, a di-lower alkylamino group, a tri-lower alkylammonio group, an amino
lower alkyl group, a lower alkylamino lower alkyl group, a di-lower alkylamino lower alkyl group, a tri-lower alky-

30 lammonio lower alkyl group, a lower alkanoylamino group, an aroylamino group, a lower alkanoylamidino lower

alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a hydroxy-
imino group and a lower alkoxyimino group, or a lower alkyl group, an aryl group or an aralkyl group which may
be substituted with one to three of said substituent(s)); Y 3 and Y 4 are each, the same or different, a single bond
or a straight-chain or branched lower alkylene group), or an lower alkyl group which may be substituted with one

35 to three of the same or different substituent(s) selected from a set of groups consisting of a lower alkyl group, a

hydroxyl group, a cyano group, halogen atoms, a nitro group, a carboxyl group, a carbamoyl group, a formyl group,
a lower alkanoyl group, a lower alkanoyloxy group, a hydroxy lower alkyl group, a cyano lower alkyl group, a halo
lower alkyl group, a carboxy lower alkyl group, a carbamoyl lower alkyl group, lower alkoxy group, a lower alkox-
ycarbonyl group, lower alkoxycarbonylamino group, a lower alkoxycarbonylamino lower alkyl group, a lower alkyl-

40 carbamoyl group, a di-lower alkylcarbamoyl group, a carbamoyloxy group, a lower alkylcarbamoyloxy group, di-

lower alkylcarbamoyloxy group, an amino group, a lower alkylamino group, a di-lower alkylamino group, a tri-lower
alkylammonio group, an amino lower alkyl group, a lower alkylamino lower alkyl group, a di-lower alkylamino lower
alkyl group, a tri-lower alkylammonio lower alkyl group, a lower alkanoylamino group, an aroylamino group, a lower
alkanoylamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylami-

45 no group, a hydroxyimino group and a lower alkoxyimino group, or a substituent selected from a set of groups

represented by the formula Y 3 -W 2 -Y 4 -R s (wherein: R s , W 2 , Y 3 and Y 4 have the same meanings as stated above),
or forms a nitrogen atom, together with X.); R 2 and R 3 are each independently, the same or different, a hydrogen
atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, or a substituent represented by the formula Y 3 -
W 2 -Y 4 -R s (wherein: R s , W 2 , Y 3 and Y 4 have the same meanings as stated above), or either R 2 or R 3 forms, together

50 with R-| and X, a saturated five- to eight-membered cyclic group selected from sets of groups of (a) and (b):

55

6

EP 1 199 306 A1

and

and the other one of R 2 or R 3 binds to a carbon atom or a nitrogen atom on the ring, or to a carbon atom, an oxygen
atom and/or a nitrogen atom on said ring-substituent of said ring to form a five- to seven-membered ring, or R 2
and R 3 are combined to form a spiro cyclo lower alkyl group, or are combined with Z on which they exist to form
an oxo (keto, orcarbonyl) group, or they (R 2 and R 3 )form, together with Z, R 1 and X to which they bind, a saturated
or an unsaturated five- to eight membered cyclic group which may be selected from sets of groups of (a) and (b):

and

, which may contain one or more kinds of hetero atom(s) selected from the group of a nitrogen atom, an oxygen
atom and a sulfur atom, or may be condensed with any of a cyclo lower alkyl group, an aryl group, a hetero aromatic
ring group selected from a set of groups consisting of an imidazolyl group, an isoxazolyl group, an isoquinolyl
group, an isoindolyl group, an indazolyl group, an indolyl group, an indolydinyl group, an isothiazolyl group, an
ethylenedioxyphenyl group, an oxazolyl group, a pyridyl group, a pyradinyl group, a pyrimidinyl group, a pyridazinyl
group, a pyrazolyl group, a quinoxalinyl group, a quinolyl group, a dihydroisoindolyl group, a dihydroindolyl group,
a thionaphthenyl group, a naphthyridinyl group, a phenazinyl group, a benzoimidazolyl group, a benzoxazolyl
group, a benzothiazolyl group, a benzotriazolyl group, a benzofuranyl group, a thiazolyl group, athiadiazolyl group,
a thienyl group, a pyrrolyl group, a furyl group, a furazanyl group, a triazolyl group, a benzodioxanyl group and a
methylenedioxyphenyl group, or an aliphatic heterocyclic group(s) selected from a set of groups comprising an
isoxazolinyl group, an isoxazolidinyl group, a tetrahydropyridyl group, an imidazolidinyl group, a tetrahydrofuranyl

EP 1 199 306 A1

group, a tetrahydropyranyl group, a piperazinyl group, a piperidinyl group, a pyrrolidinyl group, pyrrolinyl group, a
morpholino group, a tetrahydroquinolinyl group and atetrahydroisoquinolinyl group, which may be substituted with
one to three of the same or different substituent(s) selected from a set of groups consisting of a lower alkyl group,
a spiro cyclo lower alkyl group which may be substituted, a hydroxyl group, a cyano group, halogen atoms, a nitro

5 group, a carboxyl group, a carbamoyl group, a formyl group, a lower alkanoyl group, a lower alkanoyloxy group,

a hydroxy lower alkyl group, a cyano lower alkyl group, a halo lower alkyl group, a carboxy lower alkyl group, a
carbamoyl lower alkyl group, lower alkoxy group, a lower alkoxycarbonyl group, lower alkoxycarbonylamino group,
a lower alkoxycarbonylamino lower alkyl group, a lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group, a
carbamoyloxy group, a lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, an amino group, a lower

10 alkylamino group, a di-lower alkylamino group, a tri-lower alkylammonio group, an amino lower alkyl group, a lower

alkylamino lower alkyl group, a di-lower alkylamino lower alkyl group, a tri-lower alkylammonio lower alkyl group,
a lower alkanoylamino group, an aroylamino group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl
group, a loweralkylsulfonyl group, a lower alkylsulfonylamino group, a hydroxyimino group and a lower alkoxyimino
group, and a substituent selected from a set of groups represented by the formula V 1 -W 1 -Y 2 -R p (wherein: R p , W 1 ,

15 Y-) and Y 2 have the same meanings as stated above); R 4 and R 5 are each, the same or different, a hydrogen atom,

halogen atoms, a hydroxy group, an amino group, or a substituent represented by the formula Y 3 -W 2 -Y 4 -R s (where-
in: R s . W 2 , Y 3 and Y 4 have the same meanings as stated above), or any of a lower alkyl group, an aryl group or
an aralkyl group which may be substituted with one to three of the same or different substituent(s) selected from
both a set of groups consisting of a lower alkyl group, a cyano group, a nitro group, a carboxyl group, a carbamoyl

20 group, a formyl group, a lower alkanoyl group, a lower alkanoyloxy group, a hydroxy lower alkyl group, a cyano

lower alkyl group, a halo lower alkyl group, a carboxy lower alkyl group, a carbamoyl lower alkyl group, lower
alkoxy group, a lower alkoxycarbonyl group, lower alkoxycarbonylamino group, a lower alkoxycarbonylamino lower
alkyl group, a lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group, a carbamoyloxy group, a lower alkyl-
carbamoyloxy group, di-lower alkylcarbamoyloxy group, an amino group, a lower alkylamino group, a di-lower

25 alkylamino group, a tri-lower alkylammonio group, an amino lower alkyl group, a lower alkylamino lower alkyl group,

a di-lower alkylamino lower alkyl group, a tri-lower alkylammonio lower alkyl group, a lower alkanoylamino group,
an aroylamino group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl
group, a lower alkylsulfonylamino group, a hydroxyimino group and a lower alkoxyimino group, and a set of groups
represented by the formula Y 3 -W 2 -Y 4 -R s (wherein: R s , W 2 , Y 3 and Y 4 have the same meanings as stated above);

30 and the formula ™ represents either a single bond or a double bond.

[0021] Symbols and terms described in this specification are to be explained as follows.

[0022] "Nitrogen-containing heteroaromatic ring group" is an aromatic ring group which has at least one nitrogen
atom, and also an aromatic ring group which has one or more hetero atoms selected from a group consisting of an

35 oxygen atom and a sulfur atom other than the above-mentioned nitrogen atom. As specific examples of such groups,
there may be mentioned, for example, a pyridyl group, a pyrimidinyl group, a pyradinyl group, a pyridazinyl group, a
thiazolyl, a isothiazolyl. a oxazolyl, a isoxazolyl, a pyrazolyl group, a pyrrolyl group, an imidazolyl, a indolyl, a isoindolyl,
a quinolyl group, a isoquinolyl, a benzothiazolyl group or a benzoxazolyl group. Among them, a pyridyl group, a pyri-
midinyl group, a pyradinyl group, a pyridazinyl group, a thiazolyl, a pyrazolyl group, or an imidazolyl group are more

40 preferable, and a pyridyl group and a pyrazolyl group are especially preferable.

[0023] As a lower alkyl group, a straight-chain or branched chain alkyl group with one to six carbon atoms such as
a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group,
a tert-butyl group, a pentyl group and a hexyl group is preferable. Among them, a methyl group, an ethyl group and a
butyl group are more preferably employed.

45 [0024] As halogen atoms, there may be mentioned, for example, a fluorine atom, a chlorine atom, a bromine atom
and an iodine atom, more preferably, among them, a fluorine atom and a chlorine atom, and so on.
[0025] As a lower alkanoyl group, preferable is a group which may be formed by substituting a carbonyl group with
an alkyl group which consists of one to five carbon atoms. As specific examples of such groups, there may be mentioned
an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, and an isovaleryl group, a

50 pivaloyl group and a pentanoyl group. Among them, for example, an acetyl group and a propionyl group and a pivaloyl
group are more preferable.

[0026] A lower alkanoyloxy group is a group where an oxygen atom is substituted with the lower alkanoyl group
stated above. As specific examples of such groups, there may be mentioned an acetoxy group, a propionyloxy group,
a butyryloxy group, an isobutyryloxy group, a valeryloxy group, and an isovaleryloxy group, a pivaloyloxy group and a
55 pentanoyloxy group, and so on. Among them, for example, an acetoxy group and a propionyloxy group and a pivaloyloxy
group are more preferable.

[0027] As a hydroxy lower alkyl group, preferable is an alkyl group with one to six carbon atoms substituted with
hydroxyl group. Specific examples are, for example, a hydroxymethyl group, a dihydroxymethyl group, a trihydroxyme-

8

EP 1 199 306 A1

thyl group, a 1 -hydroxyethyl group, a 2-hydroxyethyl group, a 1 -hydroxypropyl group, a 2-hydroxypropyl group, a 3-hy-
droxypropyl group, a 1 -hydroxy-2- methyl ethyl group, a 1-hydroxy-2,2-dimethylethyl group, a 1 -hydroxypentyl group, a

1 - hydroxy-2-methylbutyl group, a 1 -hydroxy hexy I group, a 1-hydroxy-2-methylpentyl group, and so on. Among them,
for example, a hydroxymethyl group, a 1 -hydroxyethyl group, a 2-hydroxyethyl group and a 1 -hydroxy-2-methylethyl
group, and so on are more preferable.

[0028] As a cyano lower alkyl group, preferable is an alkyl group with one to six carbon atoms having cyano group.
Specific examples are, for example, acyanomethyl group, a 1 -cyanoethyl group, a2-cyanoethyl group, a 1 -cyanopropyl
group ; a 2-cyanopropyl group, a 3-cyanopropyl group, a 1 -cyano-2-methylethyl group, a 1 -cyanobutyl group, a 1 -cyano-

2- methylpropyl group, a 1 -cyano-2,2-dimethylethyl group, a 1 -cyanopentyl group, a 1 -cyano-2-methylbutyl group, a

1- cyanohexyl group and 1 -cyano-2-methylpentyl group, and so on. Among them, for example, a cyanomethyl group,
a 1 -cyanoethyl group, a 2-cyanoethyl group and a 1 -cyano-2-methylethyl group, and so on are more preferable.
[0029] As a halo lower alkyl group, preferable is an alkyl group with one to six carbon atoms having halo group.
Specific examples are. for example, a fluoromethyl group, a chloromethyl group, a bromomethyl group, a iodomethyl
group ; a difluoromethyl group, a dichloromethyl group, a trifluoromethyl group, 1-fluoroethyl group, a 2-fluoroethyl
group, a 1 -chloroethyl group, a 2-chloroethyl group, 1-chloropropyl group, a 2-chloropropyl group, a 1 -fluoro-2-meth-
ylethyl group, a 1-chloro-2-methylethyl group, a 1 -chlorobutyl group, a 1-chloro-2-methylpropyl group, 1-chloro-
2,2-dimethylethyl group, a 1 -chloropentyl group, a 1 -chloro-2-methylbutyl group, a 1 -chlorohexyl group, a 1-chloro-

2- methylpentyl group, and so on. Among them, for example, a chloromethyl group, a trifluoromethyl group, a 1-fluor-
oethyl group, a 1 -chloroethyl group, and a 1 -chloro-2-methylethyl group, and so on are more preferable.

[0030] As a carboxy lower alkyl group, preferable is an alkyl group with one to six carbon atoms having carboxy
group. Specific examples are, for example, a carboxymethyl group, a 1 -carboxyethyl group, a 1 -carboxypropyl group,
a 2-carboxypropyl group, a 3-carboxypropyl group, a 1 -carboxy-2-methylethyl group, a 1 -carboxybutyl group, 1-car-
boxy-2-methylpropyl group, a 1-carboxy-2,2-dimethylethyl group, a 1 -carboxypentyl group, a 1 -carboxy-2-methylbutyl
group ; 1 -carboxyhexyl group, a 1 -carboxy-2-methylpentyl group, and so on. Among them, for example, a carboxymethyl
group, a 1 -carboxyethyl group, a 2-carboxyethyl group, and a 1 -carboxy-2-methylethyl group, and so on are more
preferable.

[0031] As a carbamoyl lower alkyl group, preferable is an alkyl group with one to six carbon atoms having carbamoyl
group. Specific examples are, for example, a carbamoylmethyl group, a 1 -carbamoylethyl group, a 1 -carbamoylpropyl
group, a2-carbamoylpropyl group, a 3-carbamoylpropyl group, a 1 -carbamoyl-2-methylethyl group, a 1-carbamoylbutyl
group. 1 -carbamoyl-2-methylpropyl group, a 1 -carbamoyl-2,2-dim ethyl ethyl group, a 1 -carbamoylpentyl group, a 1 -car-
bamoyl-2-methylbutyl group, 1 -carbamoylhexyl group, a 1 -carbamoyl-2-methylpentyl group, and so on. Among them,
for example, a carbamoylmethyl group, a 1 -carbamoylethyl group, a 2-carbamoylethyl group, and a 1 -carbamoyl-
2-methylethyl group, and so on are more preferable.

[0032] As a lower alkoxy group, preferable is the one constructed by substituting an oxygen atom with an alkyl group
of one to six carbon atoms. As the specific examples, there may be mentioned a methoxy group, an ethoxy group, a
propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, asec-butoxy group, a tert-butoxy group, a
pentyloxy group, a neeopentyloxy, a hexyloxy group and an isohexyloxy group. Among them, a methoxy group, an
ethoxy group, a isopropyloxy group and a tert-butoxy group are more preferable.

[0033] A lower alkoxycarbonyl group is a group constructed by substituting an carbonyl group with an alkyl group of
one to six carbon atoms. As the specific examples, there may be mentioned a methoxycarbonyl group, an ethoxycar-
bonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl
group, a sec-butoxycarbonyl group, a tert-butoxycarbonyl group, a pentyloxycarbonyl group, a neopentyloxycarbonyl,
a hexyloxycarbonyl group and an isohexyloxycarbonyl group. Among them, a methoxycarbonyl group, an ethoxycar-
bonyl group, a isopropyloxycarbonyl group and a tert-butoxycarbonyl group are more preferable.
[0034] A lower alkylcarbamoyl group is a group constructed by substituting the nitrogen atom of a carbamoyl group
with an alkyl group mentioned above. As the specific examples, there may be mentioned, for example, a N-methylcar-
bamoyl group, a N-ethylcarbamoyl group, a N-propylcarbamoyl group, a N-isopropylcarbamoyl group, a N-butylcar-
bamoyl group, a N-isobutylcarbamoyl group, a N-tert-butylcarbamoyl group, a N-pentylcarbamoyl group, a N-hexyl-
carbamoyl group. Among them, a N-methylcarbamoyl group, a N-ethylcarbamoyl group and a N-butylcarbamoyl group
are more preferable.

[0035] A di-lower alkylcarbamoyl group is a group constructed by di-substituting the nitrogen atom of a carbamoyl
group with two lower alkyl groups stated above. As the specific examples, there may be mentioned, for example, a N,
N-dimethylcarbamoyl group, a N,N-diethylcarbamoyl group, a N,N-dipropylcarbamoyl group, a N,N-diisopropylcar-
bamoyl group, a N,N-dibutylcarbamoyl group, a N,N-diisobutylcarbamoyl group, a N,N-di-tert-butylcarbamoyl group,
a N,N-dipentylcarbamoyl group, a N,N-dihexylcarbamoyl, a N -ethyl -N-methylcarbamoyl group and a N-methyl-N-pro-
pylcarbamoyl group, and so on. Among them, for example, N, N-dimethylcarbamoyl group, a N,N-diethylcarbamoyl
group, a N,N-dibutylcarbamoyl group, a N-ethyl-N-methylcarbamoyl group and a N-methyl-N-propylcarbamoyl group,
and so on are more preferable.

EP 1 199 306 A1

[0036] A lower alkylcarbamoyloxy group is a group constructed by substituting an oxygen atom with a lower alkyl-
carbamoyl group mentioned above. As the specific examples, there may be mentioned, for example, a N-methylcar-
bamoyloxy group, a N-ethylcarbamoyloxy group, a N-propylcarbamoyloxy group, a N-isopropylcarbamoyloxy group,
a N-butylcarbamoyloxy group, a N-isobutylcarbamoyloxy group, a N-tert-butylcarbamoyloxy group, a N-pentylcar-
5 bamoyloxy group and a N-hexylcarbamoyloxy group. Among them, for example, a N-methylcarbamoyloxy group, an
N-ethylcarbamoyloxy group and a N-butylcarbamoyloxy group are more preferable.

[0037] A di-lower alkylcarbamoyloxy group is a group constructed by substituting an oxygen atom with a di-lower
alkylcarbamoyl group mentioned above. As the specific examples, there may be mentioned, for example, a N,N-dimeth-
ylcarbamoyloxy group, a N,N-diethylcarbamoyloxy group, a N-dipropylcarbamoyloxy group, a N,N-diisopropylcar-

10 bamoyloxy group, a N, N-butylcarbamoyloxy group, a N,N-diisobutylcarbamoyloxy group and a N,N-di-tert-butylcar-
bamoyloxy group, a N,N-dipentylcarbamoyloxy group, a N,N-dihexylcarbamoyloxy group and a N-ethyl-N-methylcar-
bamoyloxy group and a N-methyl-N-propylcarbamoyloxy, and so on. Among them, a N,N-dimethylcarbamoyloxy group,
a N,N-diethylcarbamoyloxy group, a N,N-dibutylcarbamoyloxy group, a N-ethyl-N-methylcarbamoyloxy group and a
N-methyl-N-propylcarbamoyloxy group, and so on are more preferable.

15 [0038] A lower alkylamino group is a group constructed by substituting an amino group with an lower alkyl group
stated above. As the specific examples, there may be mentioned, for example, a N-methylamino group, a N-ethylamino
group, a N-propylamino group, a N-isopropylamino group, a N-butylamino group, a N-isobutylamino group, a N-tert-
butylamino group, a N-pentylamino group and a N-hexylamino group. Among them, for example, a N-methylamino
group ; a N-ethylamino group and a N-butylamino group are more preferable.

20 [0039] A di-lower alkylamino group is a group constructed by N,N-di-substituting an amino group with the lower alkyl
groups. As the specific examples, there may be mentioned, for example, a N,N-dimethylammino group, a N,N-diethyl-
amino group, a N,N-dipropylamino group, a N,N-diisopropylamino group, a N,N-dibutylamino group, a N,N-di-
isobutylamino group, a N,N-di- tert-butylamino group, a N,N-dipentylamino group, a N,N-dihexylamino, a N-ethyl-N-
methylamino group and a N-methyl-N-propylamino group, and so on. Among them, for example, a N,N-dimethylamino

25 group, a N,N-diethylamino group, a N,N-dibutylamino group, a N-ethyl-N-methylamino group and a N-methyl-N-pro-
pylamino group, and so on are more preferable.

[0040] A tri-lower alkylammonio group is a group which is constructed by N ,N ,N-tri-substituting an amino group with
lower alkyl groups. As the specific exapmple, there may be mentioned, for example, a N,N,N-trimethylammonio group,
a N,N,N-triethylammonio group, a N,N,N-tripropylammonio group, a N,N,N-triisopropylammonio group, a N,N,N-trib-

30 utylammonio group, a N,N,N-triisobutylammonio group, a N,N,N-tri-tert-butylammonio group, a N,N,N-tripentylammo-
nio group, a N,N,N-trihexylammonio group and a N-ethyl-N,N-dimethylammonio group and , N,N-dimethyl-N-propy-
lammonio group, and so on. Among them, for example, a N,N,N-trimethylammonio group, a N,N,N-triethylammonio
group, a N,N,N-tributylammonio group, a N-ethyl-N,N-dimethylammonio group and a N,N-dimethyl-N-propylammonio
group ; and so on are more preferable.

35 [0041] As an amino lower alkyl group, an alkyl group of one to six carbon atoms substituted with an amino group(s)
is preferable. As the specific example, for example, there may be mentioned an aminomethyl group, a diaminomethyl
group, a triaminomethyl group group, a 1-aminoethyl group, a 2-aminoethyl group, a 1 -amino-propyl group, a 2-ami-
nopropyl group, a 3-aminopropyl group, a 1 -amino-2-methylethyl group, a 1-aminobutyl group, a 1 -amino-2-methyl-
propyl group, a 1 -amino-2,2-dimethyethyl group, a 1 -aminopentyl group and a 1 -amino-2-methylbutyl group, a 1-ami-

40 nohexyl group and a 1-amino-2-methylpentyl group, and so on. Among them, for example, an aminomethyl group, a
1-aminoethyl group, a 2-aminoethyl group and 1 -amino-2-methylethyl group, and so on, are more preferable.
[0042] A lower alkylamino lower alkyl group is a lower alkyl group substituted with a lower alkylamino group mentioned
above. As the specific examples, there may be mentioned, for example, a N -methy lam inom ethyl group, a N-ethylami-
nomethyl group, a N-propylaminomethyl group, a N-isopropylaminomethyl group, a N-butylaminomethyl group, a N-

45 isobutylaminomethyl group, a N-tert-butylaminomethyl group, a N-pentylaminomethyl group and a N-hexylaminomethyl
group, and so on. Among them, for example, a N-methylaminomethyl group, a N-ethylaminomethyl group and a N-
butylaminomethyl group, and so on, are more preferable.

[0043] A di-lower alkylamino lower alkyl group is a substituent in which a lower alkyl group is substituted with a di-
lower alkylamino group mentioned above. As the specific example, there may be mentioned, for example, a N,N-

50 dimethylaminomethyl group, a N,N-diethylaminomethyl group, a N,N-dipropylaminomethyl group, a N,N-diisopro-
pylaminomethyl group, a N,N-dibutylaminomethyl group, a N,N-diisobutylaminomethyl group, a N,N-di-tert-butylami-
nomethyl group, a N,N-dipentylaminomethyl group, a N,N-di-hexylaminomethyl group and a N-ethyl-N-methylami-
nomethyl group and N-methyl-N-propylaminomethyl group, and so on. Among them, for example, a N,N-dimethylami-
nomethyl group, a N,N-diethylaminomethyl group, a N,N-dibutylaminomethyl group, N-ethyl-N-methylaminomethyl

55 group and a N-methyl-N-propylaminomethyl group, and so on are more preferable.

[0044] A tri-lower alkylammonio lower alkyl group is a substituent in which a lower alkyl group is substituted with a
tri-lower alkylammonio group stated above. As the specific example, there may be mentioned, for example, a N,N,N-
trimethylammoniomethyl group, a N,N,N-triethylammoniomethyl group, a N,N,N-tripropylammoniomethyl group, a N,

10

EP 1 199 306 A1

N,N-triisopropylammoniomethyl group, a N,N,N-tributylammoniomethyl group, a N,N,N-triisobutylammoniomethyl
group, a N,N,N-tri-tert-butylammoniomethyl group, a N,N,N-tripentylammoniomethyl group, a N,N,N-trihexylammoni-
omethyl group and a N,N-dirnethyl-N-propylariniTionioiTiethyl group, and so on. Among them, for example, a N,N,N-
trimethylammoniomethyl group, a N,N,N-triethylammoniomethyl group, a N,N,N-tributylammoniomethyl group, N-
5 ethyl-N,N-dimethylammoniomethyl group and a N,N-dimethyl-N-propylammoniomethyl group, and so on are more pref-
erable.

[0045] A lower alkanoylamino group is a substituent in which an amino group is substituted with a lower alkanoyl
group mentioned above, being exemplified, for example, with a N-acetylamino group, a N-propionylamino group and
a N-butylylamino group, and so on. Among them, for example, N-acetylamino and N-propionylamino groups are pref-
10 erable.

[0046] A lower aroylamino group is a substituent in which an amino group is substituted with an aroyl group, being
exemplified, for example, with a N-benzoylamino group and N-naphthylamino group, and so on. Among them, for
example, a N-benzoylamino group, and so on are preferable.

[0047] A lower alkanoylamidino lower alkyl group is a substituent in which an amidino lower alkyl group is substituted
15 with a lower alkanoyl group stated above, being exemplified with, for example, a N-acetylamidinomethyl group, N-
propionylamidinomethyl group, and N-butyrylamidinomethyl group, and so on. Among them, for example, N-acetylami-
nodimethyl and N-propionylamidinomethyl groups are preferable.

[0048] A lower alkyl sulfinyl group is a substituent in which a sulfinyl group is substituted with a lower alkyl group
stated above, exemplified with, for example, a N-methyl sulfinyl group, a N-ethylsulfinyl group, and a N-butylsulfinyl

20 group, and so on. Among them, for example, N-methylsulfinyl and N-ethylsulfinyl groups are preferable.

[0049] A lower alkyl sulfonyl group is a substituent in which a sulfonyl group is substituted with a lower alkyl group
stated above, exemplified with, for example, a N-methyl sulfonyl group, a N-ethylsulfonyl group, and a N-butylsulfonyl
group, and so on. Among them, for example, N-methylsulfonyl and N-ethylsulfonyl groups are preferable.
[0050] A lower alkyl sulfonylamino group is a substituent in which an amino group is N-substituted with a lower alkyl

25 sulfonyl group stated above, exemplified with, for example, a N-methyl sulfonylamino group, a N-ethylsulfonylamino
group, and a N-butylsulfonylamino group, and so on. Among them, for example, N-methylsulfonylamino and N-ethyl-
sulfonylamino groups are preferable.

[0051] A lower alkoxyimino group is a substituent in which is substituted an imino group with a lower alkoxy group
stated above, being exemplified with a methoxyimino group, an ethoxyimino group, and a propoxyimino group. Among

30 them, for example, methoxyimino and ethoxyimino groups, and so on are preferable.

[0052] As a lower alkenyl group, a straight-chain or branched alkenyl group with two to six carbons, and so on is
preferable. As such groups, there may be mentioned, for example, a vinyl group, an allyl group, an isopropenyl group,
a 1-butenyl group, a 3-butenyl group, a1 ,3-butanedienyl group, a 2-pentenyl group, a 4-pentenyl group, a 1-hexenyl
group, a 3-hexenylgroup, a 5-hexenyl group, and so on. Among them, 1-propenyl, allyl, isopropenyl and 1-butenyl

35 groups are preferable.

[0053] As a lower alkynyl group, for example, a straight-chain or branched alkynyl group with two to six carbons is
preferable. As such alkynyl groups, there may be mentioned a 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, and so on.
Among them, 2-propynyl and a 2-butynyl are more preferable.

[0054] As a cyclo lower alkyl group, a monocyclic or bicyclic alkyl group with three to ten carbon atoms, and so on
40 is preferable. As the specific examples, there may be mentioned, for example, a cyclopropyl group, a cyclobutyl group,
a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and so on. Among them, for example,
cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups, and so on are preferable.

[0055] As an aryl group, the one aryl comprising six to fifteen carbon atoms are preferable, being exemplified with
a phenyl group and a naphthyl group, and so on. Among them, for example, a phenyl group, and so on is preferable.

45 [0056] As a heteroaromatic ring group, preferable is an imidazolyl group, an isoxazolyl group, an isoquinolyl group,
an isoindolyl group, an indazolyl group, an indolyl group, an indolydinyl group, an isothiazolyl group, an ethylenediox-
yphenyl group, an oxazolyl group, a pyridyl group, a pyradinyl group, a pyrimidinyl group, a pyridazinyl group, a pyrazolyl
group, a quinoxalinyl group, a quinolyl group, a dihydroisoindolyl group, a dihydroindolyl group, a thionaphthenyl group,
a naphthyridinyl group, a phenazinyl group, a benzoimidazolyl group, a benzoxazolyl group, a benzothiazolyl group,

50 a benzotriazolyl group, a benzofuranyl group, a thiazolyl group, a thiadiazolyl group, a thienyl group, a pyrrolyl group,
a furyl group, a furazanyl group, a triazolyl group, a benzodioxanyl group and a methylenedioxyphenyl group, and so
on. Among them, for example, an imidazolyl group, an isoxazolyl group, an isoquinolyl group, an indolyl group, an
ethylenedioxyphenyl group, a pyridyl group, a pyrimidinylgroup, a pyridazinyl group, a pyrazolyl group, a quinolyl group,
a benzoimidazolyl group, a thiazolyl group and a thienyl group are more preferable, and a pyridyl group and a pyrazolyl

55 group are especially preferable.

[0057] An aliphatic heterocyclic group is an aliphatic mono-, bi- or tricyclic heterocyclic group, which may be saturated
aliphatic heterocyclic group and an unsaturated aliphatic heterocyclic group. Specifically, for example, there may be
mentioned an isoxazolinyl group, an isoxazolidinyl group, atetrahydropyridyl group, an imidazolidinyl group, atetrahy-

11

EP 1 199 306 A1

drofuranyl group, a tetrahydropyranyl group, a piperadinyl group, a piperidinyl group, a pyrrolydinyl group, a pyrrolinyl
group, a morpholino group, atetrahydroquinolinyl group and a tetrahydroisoquinolinyl group, and so on are preferable.
Among them, for example, an isoxazolinyl group, an isoxazolidinyl group, atetrahydropyridyl group, atetrahydrofuranyl
group ; tetrahydropyranyl group, a piperadinyl group, a piperidinyl group, a pyrrolidinyl group, a morpholino group, a
5 tetrahydroisoquinolinyl groups, and so on are more preferable, and, furthermore, an isoxazolinyl group, a tetrahydro-
pyridyl group, a piperadinyl group, a piperidinyl group, a pyrrolidinyl group, a morpholino group and a tetrahydroiso-
quinolinyl group, and so on are especially preferable.

[0058] As an aralkyl group, the one aralkyl comprising seven to fifteen carbons are preferable. As specific examples,
there may be mentioned, for example, a benzyl group, an alpha-methylbenzyl group, a phenethyl group, a 3-phenyl-
10 propyl group, 1 -naphthylmethyl group, 2-naphthylmethyl group, an alpha-methyl(1-naphthyl)methyl group, an alpha-
methyl(2-naphthyl)methyl group, an alpha-ethyl(1 -naphthyl)methyl group, an alpha-ethyl(2-naphthyl)methyl group,
diphenylmethyl group and a dinaphthylmethy group, and so on, and a benzyl group, an alpha-methylbenzyl group and
a phenethyl group, and so on are especially preferable.

[0059] As a straight-chain or branched lower alkylene group, an alkylene group comprising one to six carbon atoms
15 is preferable. As the specific examples, there may be mentioned a methylene group, an ethylene group, a propylene
group, a tetramethylene group, a dimethylmethylene group, a diethylmethylene group, and so on. Among them, for
example, a methylene group, an ethylene group, a propylene group and a dimethylmethylene group, and so on are
preferable.

[0060] As a spiro cyclo lower alkyl group, an alkyl group which forms a spiro ring of three to six carbon atoms is
20 preferable. As the specific examples, there may be mentioned a spiro cyclopropyl group, a spiro cyclobutyl group, a
spiro cyclopentyl group and a spiro cyclohexyl group, and so on. Among them, a spiro cyclopentyl group and a spiro
cyclohexyl group, and so on are more preferable.

[0061] Ar represents a nitrogen-containing heteroaromatic ring group selected from a group consisting of a pyridyl
group, a pyrimidinyl group, a pyradinyl group, a pyridazinyl group, a thiazolyl group, an isothiazolyl group, an oxazolyl

25 group, an isoxazolyl group, a pyrazolyl group, a pyrrolyl group, an imidazolyl group, an indolyl group, an isoindolyl
group, a quinolyl group, an isoquinolyl group, a benzothiazolyl group and a benzoxazolyl group. Among them, for
example, a pyridyl group, a pyrimidinyl group, a pyradinyl group, a pyridazinyl group, a thiazolyl group, a pyrazolyl
group, an imidazolyl group, and so on are more preferable, and, for example, a pyridyl group and a pyrazolyl group,
and so on are especially preferable.

30 [0062] Said nitrogen-containing heteroaromatic ring group

(1) may be substituted, the same or different, with one to three substitutent(s) selected from a group consisting of
a lower alkyl group, a hydroxyl group, acyano group, halogen atoms, a nitro group, acarboxyl group, a carbamoyl
group, a formyl group, a lower alkanoyl group, a lower alkanoyloxy group, a hydroxy lower alkyl group, a cyano

35 lower alkyl group, a halo lower alkyl group, a carboxy lower alkyl group, a carbamoyl lower alkyl group, lower

alkoxy group, a lower alkoxycarbonyl group, a lower alkoxycarbonylamino group, a lower alkoxycarbonylamino
lower alkyl group, a lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group, a carbamoyloxy group, a lower
alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, an amino group, a lower alkylamino group, a di-lower
alkylamino group, atri-lower alkylammonio group, an amino lower alkyl group, a lower alkylamino lower alkyl group,

40 a di-lower alkylamino lower alkyl group, a tri-lower alkylammonio lower alkyl group, a lower alkanoylamino group,

an aroylamino group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl
group, a lower alkylsulfonylamino group, a hydroxyimino group and a lower alkoxyimino group, and the substituent
represented by a formula Y 1 -W 1 -Y 2 -R p (wherein: R p is a hydrogen atom or a lower alkyl group, a lower alkenyl
group or a lower alkynyl group optionally having one to three of said substituent(s); or a cyclo lower alkyl group,

45 an aryl group, a heteroaromatic ring group selected from a group consisting of an imidazolyl group, an isoxazolyl

group, an isoquinolyl group, an isoindolyl group, an indazolyl group, an indolyl group, an indolydinyl group, an
isothiazolyl group, an ethylenedioxyphenyl group, an oxazolyl group, a pyridyl group, a pyradinyl group, a pyrimid-
inyl group, a pyridazinyl group, a pyrazolyl group, a quinoxalinyl group, a quinolyl group, a dihydroisoindolyl group,
a dihydroindolyl group, a thionaphthenyl group, a naphthyridinyl group, a phenazinyl group, a benzoimidazolyl

50 group, a benzoxazolyl group, a benzothiazolyl group, a benzotriazolyl group, a benzofuranyl group, a thiazolyl

group, a thiadiazolyl group, a thienyl group, a pyrrolyl group, a furyl group, a furazanyl group, a triazolyl group, a
benzodioxanyl group and a methylenedioxyphenyl group, or, an aliphatic heterocyclic group selected from a set
of groups of an isoxazolinyl group, an isoxazolidinyl group, a tetrahydropyridyl group, an imidazolidinyl group, a
tetrahydrofuranyl group, a tetrahydropyranyl group, a piperazinyl group, a piperidinyl group, a pyrrolidinyl group,

55 pyrrolinyl group, a morpholino group, a tetrahydroquinolinyl group and a tetrahydroisoquinolinyl group, each of

which cyclic groups may be substituted with one to three of said substituent(s) or, furthermore, may has a bicyclic-
or tricyclic-fused ring containing the partial structure selected from a set of groups consisting of:

12

EP 1 199 306 A1

; W 1 is asinglebond, an oxygen atom, a sulfur atom, SO, S0 2 , NR q , S0 2 NR q , N(R q )S0 2 NR r , N(R q )S0 2 , CH(OR q ),
CONR q , N(R q )CO, N(R q )CONR p N(R q )COO ; N(R q )CSO, N(R q )COS, C(R q )=CR p C=C, CO, CS, OC(O), OC(O)
NR q , OC(S)NR q , SC(O), SC(0)NR q and C(0)0 (wherein: R q and R r are a hydrogen atom or a substituent selected
from a set of groups of a lower alkyl group, a cyclo lower alkyl group, a hydroxyl group, a cyano group, halogen
atoms, a nitro group, a carboxyl group, a carbamoyl group, a formyl group, a lower alkanoyl group, a lower al-
kanoyloxy group, a hydroxy lower alkyl group, a cyano lower alkyl group, a halo lower alkyl group, a carboxy lower
alkyl group, a carbamoyl lower alkyl group, lower alkoxy group, a lower alkoxycarbonyl group, lower alkoxycarb-
onylamino group, a lower alkoxycarbonylamino lower alkyl group, a lower alkylcarbamoyl group, a di-lower alkyl-
carbamoyl group, a carbamoyloxy group, a lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, an
amino group, a lower alkylamino group, a di-lower alkylamino group, a tri-lower alkylammonio group, an amino
lower alkyl group, a lower alkylamino lower alkyl group, a di-lower alkylamino lower alkyl group, a tri-lower alky-
lammonio lower alkyl group, a lower alkanoylamino group, an aroylamino group, a lower alkanoylamidino lower
alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a hydroxy-
imino group and a lower alkoxyimino group, or a lower alkyl group, an aryl group or an aralkyl group which may
be substituted with one to three of said substitutent(s).); Y 1 and Y 2 are each the same or different, a single bond
or a straight-chain or branched lower alkylene group which may have a said bicyclic or tricyclic fused ring.),
(2) may form a five- to seven-membered ring selected from a set of groups of:

which may be formed together with the carbon atom of said nitrogen-containing heteroaromatic cyclic group, on
which the substituent, which is selected from a set of groups consisting of a lower alkyl group, a lower alkanoyl
group, a lower alkanoyloxy group, a hydroxy lower alkyl group, a cyano lower alkyl group, a halo lower alkyl group,
a carboxy lower alkyl group, a carbamoyl lower alkyl group, lower alkoxy group, a lower alkoxycarbonyl group,
lower alkoxycarbonylamino group, a lower alkoxycarbonylamino lower alkyl group, a lower alkylcarbamoyl group,
a di-lower alkylcarbamoyl group, a carbamoyloxy group, a lower alkylcarbamoyloxy group, di-lower alkylcarbamoy-
loxy group, an amino group, a lower alkylamino group, a di-lower alkylamino group, a tri-lower alkylammonio group,
an amino lower alkyl group, a lower alkylamino lower alkyl group, a di-lower alkylamino lower alkyl group, a tri-
lower alkylammonio lower alkyl group, a lower alkanoylamino group, an aroylamino group, a lower alkylsulfinyl
group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, and a lower alkanoylamidino lower alkyl group
(hereinafter indicated as ring-substituent) stands, the carbon atom next to said carbon atom, and a carbon atom,
an oxygen atom and/or a nitrogen atom on said ring-substituent;

(3) may form a fifth- to seven-membered ring selected from a set of groups consisting of:

13

EP 1 199 306 A1

which may be formed together with the carbon atom of said nitrogen-containing heteroaromatic group on which a
substituent represented by the formula Y 1 -W 1 -Y 2 -R p (wherein: Y 2 and R p have the same meanings as

stated above) stands, the carbon atom next to said carbon atom, and a carbon atom, an oxygen atom and/or a
10 nitrogen atom on said ring-substituent.

[0063] Next, the forms of substituents in the category (1) will be explained in detail. As specific examples of the
substituents, there may be mentioned (1 -1) a substituent selected from a set of groups of a lower alkyl group, a hydroxyl
group ; a cyano group, halogen atoms, a nitro group, a carboxyl group, a carbamoyl group, a formyl group, a lower

*s alkanoyl group, a lower alkanoyloxy group, a hydroxy lower alkyl group, a cyano lower alkyl group, a halo lower alkyl
group ; a carboxy lower alkyl group, a carbamoyl lower alkyl group, lower alkoxy group, a lower alkoxycarbonyl group,
a lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group, a carbamoyloxy group, a lower alkylcarbamoyloxy
group, di-lower alkylcarbamoyloxy group, an amino group, a lower alkylamino group, a di-lower alkylamino group, a
tri-lower alkylammonio group, an amino lower alkyl group, a lower alkylamino lower alkyl group, a di-lower alkylamino

20 lower alkyl group, a tri-lower alkylammonio lower alkyl group, a lower alkanoylamino group, an aroylamino group, a
lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfo-
nylamino group, a hydroxyimino group and a lower alkoxyimino group; and

(1 -2) a substituent selected from a set of groups represented by a formula of Y^W^Yg-Rp (wherein: R p is a hydrogen
atom or a lower alkyl group, a lower alkenyl group or a lower alkynyl group or a cyclo lower alkyl group, an aryl group,

25 a heteroaromatic ring group or an aliphatic heterocyclic group; W-| is a single bond, an oxygen atom, a sulfur atom,
SO, S0 2 , NR q , S0 2 NR q , N(R q )S0 2 NR r , N(R q )S0 2 , CH(OR q ), CONR q , N(R q )CO, N(R q )CONR r , N(R q )COO ; N(R q )CSO,
N(R q )COS, C(R q )=CR r , CC, CO, CS, OC(O), OC(0)NR q , OC(S)NR q , SC(O), SC(0)NR q and C(0)0 (wherein: R q and
R r are each a hydrogen atom, a lower alkyl group, an aryl group or an aralkyl group which may be substituted with one
to three of said substituents); Y 1 and Y 2 are the same or different, a straight-chain or branched lower alkylene which

30 may have said bicyclic or tricyclic fused ring.), and said nitrogen-containing heteroaromatic group may be substituted
with one to three of the same or different of said substituents.

[0064] In (1-1), the more preferable substituents are, for example, a lower alkyl group, a hydroxyl group, halogen
atoms, a nitro group, a carboxyl group, a carbamoyl group, a formyl group, a lower alkanoyloxy group, a hydroxy lower
alkyl group, a halo lower alkyl group, a carbamoyl lower alkyl group, lower alkoxy group ; a lower alkoxycarbonyl group,

35 a lower alkylcarbamoyl group, a lower alkylcarbamoyloxy group, an amino group, a lower alkylamino group, a di-lower
alkylamino group, an amino lower alkyl group, a lower alkylamino lower alkyl group, a di-lower alkylamino lower alkyl
group, a lower alkanoylamino group, an aroylamino group, a lower alkylsulfonylamino group, and so on, and especially
preferable are, for example, a hydroxy group, halogen atoms, a lower alkanoyloxy group, a hydroxy lower alkyl group,
a lower alkoxy group, a lower alkoxycarbonyl group, an amino group and a lower alkylamino lower alkyl groups, and

40 so on.

[0065] In the formula Y 1 -W 1 -Y 2 -R p in (1-2), when R p is any of a lower alkyl group, a lower alkenyl group, a lower
alkynyl group, a cyclo lower alkyl group, an aryl group, a heteroaromatic ring group or an aliphatic heterocyclic group,
each of these substituents (= R p ) may be substituted to form said nitrogen-containing heteroaromatic ring substituted
with one to three of the same or different substituent(s) selected from a lower alkyl group, a hydroxyl group, a cyano

45 group, halogen atoms, a nitro group, a carboxyl group, a carbamoyl group, a formyl group, a lower alkanoyl group, a
lower alkanoyloxy group, a hydroxy lower alkyl group, a cyano lower alkyl group, a halo lower alkyl group, a carboxy
lower alkyl group, a carbamoyl lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower alkyl-
carbamoyl group, a di-lower alkylcarbamoyl group, a carbamoyloxy group, a lower alkylcarbamoyloxy group, di-lower
alkylcarbamoyloxy group, an amino group, a lower alkylamino group, a di-lower alkylamino group, a tri-lower alkylam-

so monio group, an amino lower alkyl group, a lower alkylamino lower alkyl group, a di-lower alkylamino lower alkyl group,
a tri-lower alkylammonio loweralkyl group, a lower alkanoylamino group, an aroylamino group, a lower alkanoylamidino
lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a hydrox-
yimino group and a lower alkoxyimino group.

[0066] In cases where R p is a cyclo lower alkyl group, an aryl group, a heteroaromatic ring group or an aliphatic
55 heterocyclic group, each of these groups may have, in addition to the substituents described above, a bicyclic ortricyclic
fused ring having a partial structure selected from a set of groups of:

14

EP 1 199 306 A1

O , (!) a„ a c!>

5

[0067] In the formula Y 1 -W 1 -Y 2 -R p) W 1 is a single bond ; an oxygen atom, a sulfur atom, SO, S0 2 , NR q! S0 2 NR q! N
(R q )S0 2 NR r , N(R q )S0 2 , CH(OR q ), CONR q , N(R q )CO, N(R q )CONR p N(R q )COO, N(R q )CSO, N(R q )COS, C(R q )=CR r ,
C=C, CO, CS, OC(O), OC(0)NR q , OC(S)NR q , SC(O), SC(0)NR q and C(0)0 (wherein: R q and R r are hydrogen atom
or a substituent selected from a set of groups of a lower alkyl group, a cyclo lower alkyl group, a hydroxyl group, a

10 cyano group, halogen atoms, a nitro group, a carboxyl group, a carbamoyl group, a formyl group, a lower alkanoyl
group ; a lower alkanoyloxy group, a hydroxy lower alkyl group, a cyano lower alkyl group, a halo lower alkyl group, a
carboxy lower alkyl group, a carbamoyl lower alkyl group, lower alkoxy group, a lower alkoxycarbonyl group, lower
alkoxycarbonylamino group, a lower alkoxycarbonylamino lower alkyl group, a lower alkylcarbamoyl group, a di-lower
alkylcarbamoyl group, a carbamoyloxy group, a lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, an

*s amino group, a lower alkylamino group, a di-lower alkylamino group, a tri-lower alkylammonio group, an amino lower
alkyl group, a lower alkylamino lower alkyl group, a di-lower alkylamino lower alkyl group, a tri-lower alkylammonio
lower alkyl group, a lower alkanoylamino group, an aroylamino group, a lower alkanoylamidino lower alkyl group, a
lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a hydroxyimino group and a
lower alkoxyimino group, or a lower alkyl group, an aryl group or an aralkyl group which may be substituted with one

20 to three of said substituents.). Among them, an oxygen atom, a sulfur atom, NR q , S0 2 NR q , N(R q )S0 2 , CONR q , N(R q )
CO, N(R q )COO, C(R q )=CR r , OC(O), OC(0)NR q , C(0)0, and so on, are more preferable and NR q , N(R q )S0 2 , CONR q ,
N(R q )CO, N(R q )COO, OC(O), C(0)0, and so on are especially preferable.

[0068] Furthermore, R q and R r in W 1 are each a hydrogen atom or a substituent selected from a set of groups,
namely, a lower alkyl group, a cyclo lower alkyl group, a hydroxyl group, a cyano group, halogen atoms, a nitro group,
25 a carboxyl group, a carbamoyl group, a formyl group, a lower alkanoyl group, a lower alkanoyloxy group, a hydroxy
lower alkyl group, a cyano lower alkyl group, a halo lower alkyl group, a carboxy lower alkyl group, a carbamoyl lower
alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, lower alkoxycarbonylamino group, a lower alkoxycar-
bonylamino lower alkyl group, a lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group, a carbamoyloxy group,
a lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, an amino group, a lower alkylamino group, a di-
sc lower alkylamino group, a tri-lower alkylammonio group, an amino lower alkyl group, a lower alkylamino lower alkyl
group, a di-lower alkylamino lower alkyl group, a tri-lower alkylammonio lower alkyl group, a lower alkanoylamino group,
an aroylamino group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group,
a lower alkylsulfonylamino group, a hydroxyimino group and a lower alkoxyimino group, or a lower alkyl group, an aryl
group or an aralkyl group, which may be substituted with one to three of said substituent(s). Said lower alkyl group,
35 said aryl group, or said aralkyl group may be substituted with one to three substituent(s) selected from a set of groups
of, a lower alkyl group, a hydroxyl group, a cyano group, halogen atoms, a nitro group, a carboxyl group, a carbamoyl
group, a formyl group, a lower alkanoyl group, a lower alkanoyloxy group, a hydroxy lower alkyl group, a cyano lower
alkyl group, a halo lower alkyl group, a carboxy lower alkyl group, a carbamoyl lower alkyl group, lower alkoxy group,
a lower alkoxycarbonyl group, a lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group, a carbamoyloxy group,
40 a lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, an amino group, a lower alkylamino group, a di-
lower alkylamino group, a tri-lower alkylammonio group, an amino lower alkyl group, a lower alkylamino lower alkyl
group, a di-lower alkylamino lower alkyl group, a tri-lower alkylammonio lower alkyl group, a lower alkanoylamino group,
an aroylamino group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group,
a lower alkylsulfonylamino group, a hydroxyimino group and a lower alkoxyimino group.
45 [0069] In the formula Y-|-W-|-Y2-Rp, Y-| and Y 2 are each of same or different, a single bond or a straight-chain or
branched lower alkylene. Said straight-chain or branched lower alkylene may have a bicyclic or tricyclic fused ring
containing a partial structure selected from the set of groups;

O . O - 6

[0070] Next, theforms of the substituent in (2) will be explained in detail. This substituent is afive-to seven-membered
55 ring selected from a set of groups:

15

EP 1 199 306 A1

which may be formed together with the carbon atom of said nitrogen-containing heteroaromatic cyclic group, on which
the substituent, which is selected from a set of groups consisting of a lower alkyl group, a lower alkanoyl group, a lower
alkanoyloxy group, a hydroxy lower alkyl group, a cyano lower alkyl group, a halo lower alkyl group, a carboxy lower
alkyl group, a carbamoyl lower alkyl group, lower alkoxy group, a lower alkoxycarbonyl group, lower alkoxycarbonylami-
no group, a lower alkoxycarbonylamino lower alkyl group, a lower alkylcarbamoyl group, a di-lower alkylcarbamoyl
group, a carbamoyloxy group, a lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, an amino group,
a lower alkylamino group, a di-lower alkylamino group, a tri-lower alkylammonio group, an amino lower alkyl group, a
lower alkylamino lower alkyl group, a di-lower alkylamino lower alkyl group, a tri-lower alkylammonio lower alkyl group,
a lower alkanoylamino group, an aroylamino group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower
alkylsulfonylamino group, and a lower alkanoylamidino lower alkyl group stands, the carbon atom next to said carbon
atom, and a carbon atom, an oxygen atom and/or a nitrogen atom on said ring-substituent.

[0071] Furthermore, among said ring-substituents, more preferable are a lower alkyl group, a lower alkanoyloxy
group, a hydroxy lower alkyl group, a halo lower alkyl group, a carbamoyl lower alkyl group, a lower alkoxy group, a
lower alkoxycarbonyl group, a lower alkylcarbamoyl group, a lower alkylcarbamoyloxy group, a lower alkylamino group,
a di-lower alkylamino group, an amino lower alkyl group, a lower alkylamino lower alkyl group, a di-lower alkylamino
lower alkyl group, a lower alkanoylamino group, an aroylamino group, and so on. Among them, especially preferable
are a lower alkanoyloxy group, a hydroxy lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a
lower alkylamino lower alkyl group, and so on.

[0072] Next the forms of the substituents (3) will be explained in detail. This substituent is a five- to seven-membered
ring, and so on, which may be selected from a set of groups:

which may be formed by the participation of the ring-carbon atom on a ring which the substituent of the formula
W-i-Yg-Rp (wherein: Y 1; W 1; Y 2 and R p have the same meanings as mentioned above) bind to, the carbon atom next
to said carbon atom, and a carbon atom, an oxygen atom and/or a nitrogen atom on said ring-substituent.
[0073] Although all said substituents and groups constructed on said nitrogen-containing heteroaromatic ring groups
of (1), (2) and (3) are preferable, more preferable forms of them are:

(1 ') a substituent selected from both the set of groups consisting of a lower alkyl group, a hydroxyl group, halogen
atoms, aformyl group, a lower alkanoyloxy group, a hydroxy lower alkyl group, a halo lower alkyl group, a carbamoyl
lower alkyl group, lower alkoxy group, a lower alkoxycarbonyl group, a lower alkylcarbamoyl group, a lower alkyl-
carbamoyloxy group, an amino group, a lower alkylamino group, a di-lower alkylamino group, an amino lower alkyl
group, a lower alkylamino lower alkyl group, a di-lower alkylamino lower alkyl group, a lower alkanoylamino group,
an aroylamino group and a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a hydroxyimino group and
a lower alkoxyimino group, and a substituent represented by a formula Y 1a -W 1a -Y 2a -R pa (wherein: R pa is a hydro-

and

16

EP 1 199 306 A1

gen atom or a lower alkyl group, a lower alkenyl group or a lower alkynyl group which may be substituted with one
to three of said substituents or a cyclo lower alkyl group, an aryl group, a heteroaromatic ring group selected from
a set of groups of an imidazolyl group, an isoxazolyl group, an isoquinolyl group, an indolyl group, an ethylenedi-
oxyphenyl group, a pyridyl group, an pyrimidinyl group, a pyridazinyl group, a pyrazolyl group, a quinolyl group, a
benzoimidazolyl group, a thiazolyl group, a thienyl and a triazolyl group, and an aliphatic heterocyclic group se-
lected from a set of groups of an isoxazolinyl group, an isoxazolidinyl group, a tetra hydro pyridyl group, atetrahy-
drofuranyl group, a tetrahydropyranyl group, a piperadinyl group, a piperidinyl group, a pyrrolidinyl group, a mor-
pholino group and a tetrahydroisoquinolinyl group, which may be substituted with one to three of said substituent
(s) and may, furthermore, have a bicyclic or a tricyclicfused ring of a partial structure selected from a set of structures
of:

O , 6 _ &

and

; W 1a is an oxygen atom, a sulfur atom, NR qa , S0 2 NR qa , N(R qa )S0 2 , CONR qa , N(R qa )CO, N(R qa )COO, C(R qa )
=CR ra , OC(O), OC(0)NR qa , and C(0)0 (wherein R qa and R ra are each either a substituent selected from a set of
groups of a hydrogen atom, a lower alkyl group, a cyclo lower alkyl group, a hydroxyl group, halogen atoms, a
formyl group, a lower alkanoyloxy group, a hydroxy lower alkyl group, a halo lower alkyl group, a carbamoyl lower
alkyl group, lower alkoxy group, a lower alkoxycarbonyl group, lower alkoxycarbonylamino group, a lower alkox-
ycarbonylamino lower alkyl group, a lower alkylcarbamoyl group, a lower alkylcarbamoyloxy group, an amino
group, a lower alkylamino group, a di-lower alkylamino group, an amino lower alkyl group, a lower alkylamino lower
alkyl group, a di-lower alkylamino lower alkyl group, a lower alkanoylamino group, an aroylamino group, and a
lower alkylsulfonylamino group or a lower alkyl group, an aryl group or an aralkyl group which may be substituted
with said substituent(s)); Y 1a and Y 2a are the same or different, a single bond or a straight-chain or branched lower
alkylene group which may have a said bicyclic or tricyclic fused ring;

(2 1 ) a nitrogen-containing heteroaromatic ring group which has a condensed five- or six-membered ring selected
from the group of rings:

, which are formed together with the ring-carbon atom on said heterocyclic ring on which the ring-substituent
selected from a set of groups of a lower alkyl group, a lower alkanoyloxy group, a hydroxy lower alkyl group, a
halo lower alkyl group, a carbamoyl ower alkyl group, a lower alkoxy group, a lower alkoxycarbaonyl group, a lower
alkylcarbamoyl group a lower alkylcarbamoyloxy group, a lower alkylamino group, a di-loser alkylamino group, an
amino lower alkyl group, a lower alkylamino lower alkyl group, a di-lower alkylamino lower alkyl group, a lower
alkanoylamino group and an aroylamino group stands, the carbon atom next to said carbon atom, and a carbon
atom, an oxygen atom and/or a nitrogen atom on said ring-substituent;
or,

(3 1 ) a fused five- or six-membered ring selected from a group of rings:

0.6.0 . O- O

, which are formed together with the ring-carbon atom which the substituent represented by the formula of Y 1a -
W 1a -Y 2a -R pa (wherein: Y 1a , W 1a , Y 2a and R pa have the same meanings as stated above) binds to, the carbon atom
next to said carbon atom, and a carbon atom, an oxygen atom and/or a nitrogen atom on said substituent.

rthermore, the more preferable substituent groups are:

(1") a substituent selected from the group consisting from a hydroxy group, halogen atoms, a lower alkanoyloxy
group, a hydroxy lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, an amino group and a

17

EP 1 199 306 A1

lower alkylamino lower alkyl group, and a group represented by a formula Y-i b -W 1b -Y 2b -R pb (wherein: R pb is a
hydrogen atom or a lower alkyl group, a lower alkenyl group or a lower alkynyl group which are optionally substituted
with one to three of said substituent(s), or a cyclo lower alkyl group, an aryl group, a heteroaromatic ring group
selected from a set of groups of a pyridyl group and a pyrazolyl group or an aliphatic heterocyclic group selected
from a set of groups of an isoxazolinyl group, a tetrahydropyridyl group, a piperadinyl group, a piperidinyl group,
a pyrrolidinyl group, a m and ino group and a tetrahydroisoquinolinyl group, which may be substituted with one to
three said substituent and which may have bicyclic or tricyclic fused ring containing partial structure selected from
a group of;

; W 1b is a NR qb , N(R qb )S0 2 , CONR qb , N(R qb )CO, N(R qb )COO, OC(O) or C(0)0 (wherein: R qb and R rb are each
a hydrogen atom or a substituent selected from a set of groups which consists of a hydroxyl group, halogen atoms,
a lower alkanoyloxy group, a hydroxy lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, an
amino group and a lower alkylamino lower alkyl group, or a lower alkyl group, an aryl group or an aralkyl group
which may be substituented with one to three of said substituent(s)); Y 1b and Y 2b are each, the same or different,
a single bond or a straight-chain or branched lower alkylene group which may have a said bicyclic or tricyclic fused
ring.)

(2") a five- or six-membered ring selected from a group of:

0.6,0.0

and

which is formed together with a ring-carbon atom to which a substituent selected from a set of groups of a lower
alkanoyloxy group, a hydroxy lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group and a lower
alkylamino lower alkyl group binds, the carbon atom next to said carbon atom, and a carbon atom, an oxygen atom
and/or a nitrogen atom on said substituent,; or
(3") a five- or six-membered ring selected from a group of:

which is formed together with a ring-carbon atom to which a substituent represented by the formula Yi b -W 1b -Y 2b -
R pb (wherein: Y-| b , W 1b , Y 2b and R pb have the same meanings as stated above) binds, the carbon atom next to
said carbon atom and a carbon atom, an oxygen atom and/or a nitrogen atom of said substituent.

[0074] X and Z are each, the same or different, either a carbon atom or a nitrogen atom, or, if approproate, a CH or
a nitrogen atom together with the R.,, R 2 and/or R 3 which they bind to.
[0075] Y is CO, SO or S0 2

[0076] R-| is a hydrogen atom or a substituent represented by a formula Y 3 -W 2 -Y 4 -R s (wherein: R s is a hydrogen
atom or a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cyclo lower alkyl group, an aryl group, or
a heteroaromatic ring group selected from a set of groups of an imidazolyl group, an isoxazolyl group, an isoquinolyl
group, an isoindolyl group, an indazolyl group, an indolyl group, an indolydinyl group, an isothiazolyl group, an ethyl-
enedioxyphenyl group, an oxazolyl group, a pyridyl group, apyradinyl group, a pyrimidinyl group, a pyridazinyl group,
a pyrazolyl group, a quinoxalinyl group, a quinolyl group, a dihydroisoindolyl group, a dihydroindolyl group, athionaph-
thenyl group, a naphthyridinyl group, a phenazinyl group, a benzoimidazolyl group, a benzoxazolyl group, a benzothi-
azolyl group, a benzotriazolyl group, a benzofuranyl group, a thiazolyl group, a thiadiazolyl group, a thienyl group, a
pyrrolyl group, afuryl group, afurazanyl group, atriazolyl group, a benzodioxanyl group and a methylenedioxyphenyl

18

EP 1 199 306 A1

group, or an aliphatic heterocyclic group selected from a set of groups of an isoxazolinyl group, an isoxazolidinyl group,
a tetrahydropyridyl group, an imidazolidinyl group, a tetrahydrofuranyl group, a piperazinyl group, a piperidinyl group,
a pyrrolidinyl group, pyrrolinyl group, a morpholino group, a tetrahydroquinolinyl group and a tetrahydroisoquinolinyl
group ; which may be substituted with one to three of said substituent(s); W 2 is a single bond, an oxygen atom, a sulfur

5 atom, SO, S0 2 , NR t , S0 2 NR t , N(R t )S0 2 NR u , N(R t )S0 2 , CH(OR t ), CONR t , N(R t )CO, N(R t )CONR u , N(R t )COO, N(R t )
CSO, N(R t )COS, C(R v )=CR r , C=C, CO, CS, OC(O), OC(0)NR t , OC(S)NR t , SC(O), SC(0)NR t or C(0)0 (wherein:
each of R t and R u is a hydrogen atom or a substituent selected from a set of groups of a lower alkyl group, a hydroxyl
group ; a cyano group, halogen atoms, a nitro group, a carboxyl group, a carbamoyl group, a formyl group, a lower
alkanoyl group, a lower alkanoyloxy group, a hydroxy lower alkyl group, a cyano lower alkyl group, a halo lower alkyl

10 group, a carboxy lower alkyl group, a carbamoyl lower alkyl group, lower alkoxy group, a lower alkoxycarbonyl group,
a lower alkoxycarbonylamino group, a lower alkoxycarbonylamino lower alkyl group, a lower alkylcarbamoyl group, a
di-lower alkylcarbamoyl group, a carbamoyloxy group, a lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy
group, an amino group, a lower alkylamino group, a di-lower alkylamino group, a tri-lower alkylammonio group, an
amino lower alkyl group, a lower alkylamino lower alkyl group, a di-lower alkylamino lower alkyl group, a tri-lower

15 alkylammonio lower alkyl group, a lower alkanoylamino group, an aroylamino group, a lower alkanoylamidino lower
alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a hydroxyimino
group and a lower alkoxyimino group, or a lower alkyl group, an aryl group or an aralkyl group, which may be substituted
with one to three of said substituent(s)); Y 3 and Y 4 are each, the same or different, a single bond or a straight-chain
or branched lower alkylene), or a lower alkyl group which may be substituted with one to three of the same or different

20 substituent(s) selected from both a set of groups of a lower alkyl group, a hydroxyl group, a cyano group, halogen
atoms, a nitro group, a carboxyl group, a carbamoyl group, a formyl group, a lower alkanoyl group, a lower alkanoyloxy
group, a hydroxy lower alkyl group, a cyano lower alkyl group, a halo lower alkyl group, a carboxy lower alkyl group,
a carbamoyl lower alkyl group, lower alkoxy group, a lower alkoxycarbonyl group, a lower alkylcarbamoyl group, a di-
lower alkylcarbamoyl group, a carbamoyloxy group, a lower alkylcarbamoyloxy group, a di-lower alkylcarbamoyloxy

25 group, an amino group, a lower alkylamino group, a di-lower alkylamino group, a tri-lower alkylammonio group, an
amino lower alkyl group, a lower alkylamino lower alkyl group, a di-lower alkylamino lower alkyl group, a tri-lower
alkylammonio lower alkyl group, a lower alkanoylamino group, an aroylamino group, a lower alkanoylamidino lower
alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a hydroxyimino
group and a lower alkoxyimino group, and a set of groups represented by the formula Y 3 -W 2 -Y 4 -R s (wherein: R s , W 2 ,

30 y 3 and Y 4 have the same meanings as stated above); or forms a nitrogen atom together with X.

[0077] Here comes a detailed explanation of the various forms of R^ Thus, R 1 is a hydrogen atom or a substituent
represented by the formula Y 3 -W 2 -Y 4 -R s (wherein: R s , W 2 , Y 3 and Y 4 have the same meanings as stated above), or
a lower alkyl group which may be substituted with one to three of the same or different substituent(s), orforms a nitrogen
atom together with X.

35 [0078] Regarding the formula Y 3 -W 2 -Y 4 -R s , R s is a lower alkyl group, a lower alkenyl group, a lower alkynyl group,
a cyclo lower alkyl group, an aryl group, a heteroaromatic ring group, or an aliphatic heterocyclic group, and so on,
and each of these substituents may, optionally, be substituted with one to three substituent(s) selected from a set of
groups of a lower alkyl group, a hydroxyl group, a cyano group, halogen atoms, a nitro group, a carboxyl group, a
carbamoyl group, a formyl group, a lower alkanoyl group, a lower alkanoyloxy group, a hydroxy lower alkyl group, a

40 cyano lower alkyl group, a halo lower alkyl group, a carboxy lower alkyl group, a carbamoyl lower alkyl group, lower
alkoxy group, a lower alkoxycarbonyl group, a lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group, a car-
bamoyloxy group, a lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, an amino group, a lower
alkylamino group, a di-lower alkylamino group, a tri-lower alkylammonio group, an amino lower alkyl group, a lower
alkylamino lower alkyl group, a di-lower alkylamino lower alkyl group, a tri-lower alkylammonio lower alkyl group, a

45 lower alkanoylamino group, an aroylamino group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group,
a lower alkylsulfonyl group, a lower alkylsulfonylamino group : a hydroxyimino group and a lower alkoxyimino group.
As more preferable substituents, there may be mentioned the same ones as those mentioned as the substituents on Ar.
[0079] With the formula Y 3 -W 2 -Y 4 -R s , W 2 is a single bond, an oxygen atom, a sulfur atom, SO, S0 2 , NR t , S0 2 NR t ,
N(R t )S0 2 NR u , N(R t )S0 2 , CH(OR t ), CONR t , N(R t )CO, N(R t )CONR u , N(R t )COO, N(R t )CSO, N(R t )COS, C(R v )=CR r ,

so C=C, CO, CS, OC(O), OC(0)NR t , OC(S)NR t , SC(O), SC(0)NR t and C(0)0, wherein R t and R u are each a hydrogen
atom or a substituent selected from a set of groups of a lower alkyl group, a hydroxyl group, a cyano group, halogen
atoms, a nitro group, a carboxyl group, a carbamoyl group, a formyl group, a lower alkanoyl group, a lower alkanoyloxy
group, a hydroxy lower alkyl group, a cyano lower alkyl group, a halo lower alkyl group, a carboxy lower alkyl group,
a carbamoyl lower alkyl group, lower alkoxy group, a lower alkoxycarbonyl group, lower alkoxycarbonylamino group,

55 a lower alkoxycarbonylamino lower alkyl group, a lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group, a
carbamoyloxy group, a lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, an amino group, a lower
alkylamino group, a di-lower alkylamino group, a tri-lower alkylammonio group, an amino lower alkyl group, a lower
alkylamino lower alkyl group, a di-lower alkylamino lower alkyl group, a tri-lower alkylammonio lower alkyl group, a

19

EP 1 199 306 A1

lower alkanoylamino group, an aroylamino group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group,
a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a hydroxyimino group and a lower alkoxyimino group,
or a lower alkyl group, an aryl group or an aralkyl group which may be substituted with one to three of said substituent
(s). Furthermore, each

5 of said lower alkyl group, said aryl group and said aralkyl group may be substituted with one to three of said substituent
(s) as R s may be.

[0080] With the formula Y 3 -W 2 -Y 4 -R s , Y 3 and Y 4 are each, the same or different, a single bond or a straight-chain
or branched lower alkylene group.

[0081] As more preferable examples of R 1 , there may be mentioned, for example, a hydrogen or a lower alkyl which

10 may be substituted with one to three of same or different substituent(s) selected from a substituent represented by a
formula Y 3a -W 2a -Y 4a -R sa (wherein: R sa is a hydrogen atom or a lower alkyl group, a lower alkenyl group, a cyclo lower
alkyl group, an aryl group, a heteroaromatic ring group selected from an indolyl group, or an aliphatic heterocyclic
group selected from a set of groups of a tetrahydropyridyl group, a piperadinyl group, a piperidinyl group, a pyrrolidinyl
group and a morpholino group ; all of which groups may be substituted with one to three of said substituent(s); W 2a is

15 a single bond, NR ta , CH(OR ta ), CONR ta , N(R ta )CO, N(R ta )COO, OC(0)NR ta or C(0)0 (wherein: R ta and R ua are each
a hydrogen atom or a lower alkyl group, an aryl group or an aralkyl group which may be substituted with one to three
of said substituent(s)); Y 3a and Y 4a are each, the same or different, a single bond, or a straight-chain or branched lower
alkylene group), or a lower alkyl group which may be substituted with one to three of the same or different substituent
(s) selected from both a set of groups of a lower alkyl group, a hydroxyl group, a carbamoyl group, a lower alkanoyloxy

20 group, a hydroxy lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower alkylcarbamoyl group,
a di-lower alkylcarbamoyl group, a carbamoyloxy group, a lower alkylcarbamoyloxy group, a lower alkylamino group,
a di-lower alkylamino group, an amino lower alkyl group, a lower alkylamino lower alkyl group, a di-lower alkylamino
lower alkyl group, a lower alkanoylamino group and an aroylamino group), and a substituent represented by the formula
^3a"^2a"^4a" ^ S a (wherein: R sa , W 2a , Y 3a and Y 4a have the same meanings as stated above). R 1 may also preferably

25 form a nitrogen atom together with X. And, as the especially preferable examples of R-|, there may be mentioned a
hydrogen or a lower alkyl group which may be substituted with one to three of the same or different substituent(s)
selected from a substituent represented by a formula Y 3b -W 2b -Y 4b -R sb (wherein: R sb is a hydrogen atom or a lower
alkyl group, a cyclo lower alkyl group and an aryl group which may be substituted with one to three of said substituent
(s); W 2b is a single bond, N(R tb )COO or C(0)0 (wherein R tb is a hydrogen atom, a lower alkyl group, an aryl group or

30 an aralkyl group which may be substituted with one to three of said substituent(s)); Y 3b and Y 4b are respectively, the
same or different, a single bond, a straight-chain or branched lower alkylene or a hydroxy lower alkyl group) and a
substituent represented by the formula Y 3b -W 2b -Y 4b -R sb (wherein: R sb , W 2b , Y 3b and Y 4b have the same ineanings as
stated above)). R-| also forms, very preferably, a nitrogen atom together with X.
[0082] R 2 and R 3 are each independently, the same or different:

35

(i) a hydrogen, a hydroxy group, a lower alkyl group, a lower alkoxy group, or a substituent represented by the
formula Y 3 -W 2 -Y 4 -R s (wherein: R s , W 2 , Y 3 and Y 4 have the same meanings as stated above), or

(ii) either R 2 or R 3 forms, together with R-| and X, a saturated five- to eight-membered cyclic group selected from
groups of (a) and (b):

40

45

50

and

s\ <A N A

O • O • Wand O

, the other (remaining) one forming a five- to seven-membered ring together with a ring carbon atom or a ring

20

EP 1 199 306 A1

nitrogen atom, and a carbon atom, an oxygen atom and/or a nitrogen atom in the ring-substituent on said ring, or
(iii) R 2 and R 3 , being taken together, form a spiro cyclo lower alkyl group, and also form an oxo group together
with Z to which they bind, or form, together with Zto which they bind, R 1 and X, either a saturated or an unsaturated
five- to eight-membered cyclic group selected from sets of groups of (a) and (b)

which may both contain one or more kinds of heteroatoms selected from a group of a nitrogen atom, an oxygen
atom and a sulfur atom and which may be substituted with one to three of the same or different substituent(s)
selected from both a set of groups of a lower alkyl group, a spiro cyclo lower alkyl group which may be substituted,
a hydroxy group, a cyano group, halogen atoms, a nitro group, a carboxyl group, a carbamoyl group, a formyl
group, a lower alkanoyl group, a lower alkanoyloxy group, a hydroxy lower alkyl group, a cyano lower alkyl group,
a halo lower alkyl group, a carboxy lower alkyl group, carbamoyl lower alkyl group, a lower alkoxy group, a lower
alkoxycarbonyl group, a lower alkoxycarbonylamino group, a lower alkoxycarbonylamino lower alkyl group, a lower
alkyl carbamoyl group, di-lower alkyl carbamoyl group, a carbamoyloxy group, a lower alkylcarbamoyloxy group,
di-lower alkyl carbamoyloxy group, and amino group, a lower alkylamino group, di-lower alkylamino group, tri-
lower alkylammonio group, an amino lower alkyl group, a lower alkylamino lower alkyl group ; di-lower alkylamino
lower alkyl group, tri-lower alkylammonio lower alkyl group, a lower alkanoylamino group, an aroylamino group, a
lower alkanoylamidino lower alkyl group, a lower alkyl sulfinyl group, a lower alkylsulfonyl group, a lower alkylsul-
fonylamino group, a hydroxyimino group and a lower alkoxyimino group, and a set of substituents represented by
the formula Y 1 -W 1 -Y 2 -R p (wherein: R p , W 1 , Y 1 and Y 2 have the same meanings as stated above), and furthermore
may be fused with a cyclo alkyl group, an aryl group, a hetero aromatic ring group selected from a set of groups
of an imidazolyl group, an isoxazolyl group, an isoquinolyl group, an isoindolyl group, an indazolyl group, an indolyl
group, an indolydinyl group, an isothiazolyl group, an ethylenedioxyphenyl group, an oxazolyl group, a pyridyl
group, a pyradinyl group, a pyrimidinyl group, a pyridazinyl group, a pyrazolyl group, a quinoxalinyl group, a quinolyl
group, a dihydroisoindolyl group, a dihydroindolyl group, a thionaphthenyl group, a naphthyridinyl group, a phen-
azinyl group, a benzoimidazolyl group, a benzoxazolyl group, a benzothiazolyl group, a benzotriazolyl group, a
benzofuranyl group, a thiazolyl group, a thiadiazolyl group, a thienyl group, a pyrrolyl group, a furyl group, a fura-
zanyl group, a triazolyl group, a benzodioxanyl group and a methylenedioxyphenyl group, and an aliphatic hete-
rocyclic group(s) selected from an isoxazolinyl group, an isoxazolidinyl group, a tetrahydropyridyl group, an imi-
dazolidinyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a piperazinyl group, a piperidinyl group,
a pyrrolidinyl group, pyrrolinyl group, amorpholinogroup, atetrahydroquinolinyl group andatetrahydroisoquinolinyl
group, which may be substituted with one to three of the same or different substituent(s).

[0083] Here. R 2 and R 3 are explained more specifically as follows. The present invention includes all of the three
cases where (i) each of the R 2 and R 3 has, the same or different, a substituent, independently; (ii) either R 2 or R 3 forms
a substituent together with other substituent(s), followed by the formation of a second substituent between the substit-
uent formed and the remaining R 2 or R 3 group; and (iii) both R 2 and R 3 work together or further collaborate with other
substituent(s) and so on, to form a substituent.

21

EP 1 199 306 A1

[0084] Next each form of the substituents R 2 and R 3 is explained.

(i) R 2 and R 3 are each, the same or different and independently, a hydrogen atom, a hydroxy group, a lower alkyl
group, a lower alkoxy group, or a substituent which is represented by the formula Y 3 -W 2 -Y 4 -R s (wherein. R s , W 2 ,
Y 3 and Y 4 have the meanings stated above);

(ii) either R 2 or R 3 forms, together with R 1 and X ; a saturated five- to eight-membered ring selected from sets of
groups (a) and (b):

(a)

O , O O ■

o o 0°

N — ' ' S — ' ' N — '

(b)

N

and

and the remaining group, R 2 or R 3 , may form a five- to seven-membered ring, together with said five- to eight-
membered ring, by collaborating with a carbon atom or a nitrogen atom on said ring, and a carbon atom, an oxygen
atom and/or a nitrogen atom in the ring-substituent on said ring.

(iii) R 2 and R 3 may (iii-1) work together to form a spiro cyclo lower alkyl group, or (iii-2) form an oxo (keto or
carbonyl) group together with Z which they bind to, or (iii-3) form, together with Z which they bind to, R-| and X, a
saturated or an unsaturated five- to eight-membered ring selected from sets of groups of (a) and (b):

00

O ,O.Q ,r>, O.

o o C°

N — '

(b)

and

which may contain one or more kinds of hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur
atom,

[0085] Said saturated or unsaturated five- to eight-membered rings may be substituted with one to three of the same
or different substituent(s) selected from both a set of groups of a lower alkyl group, a spiro cyclo lower alkyl group

22

EP 1 199 306 A1

which may have a substituent(s), a hydroxyl group, a cyano group, halogen atoms, a nitro group, a carboxyl group, a
carbamoyl group, a formyl group, a lower alkanoyl group, a lower alkanoyloxy group, a hydroxy lower alkyl group, a
cyano lower alkyl group, a halo lower alkyl group, a carboxy lower alkyl group, a carbamoyl lower alkyl group, lower
alkoxy group, a lower alkoxycarbonyl group, lower alkoxycarbonylamino group, a lower alkoxycarbonylamino lower

5 alkyl group, a lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group, a carbamoyloxy group, a lower alkylcar-
bamoyloxy group, di-lower alkylcarbamoyloxy group, an amino group, a lower alkylamino group, a di-lower alkylamino
group, a tri-lower alkylammonio group, an amino lower alkyl group, a lower alkylamino lower alkyl group, a di-lower
alkylamino lower alkyl group, a tri-lower alkylammonio lower alkyl group, a lower alkanoylamino group, an aroylamino
group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkyl-

10 sulfonylamino group, a hydroxyimino group and a lower alkoxyimino group, and a set of groups of substituent repre-
sented by a formula Y-pW-i-Y^Rp (wherein: R p , W-,, Y-| and Y 2 have the same meanings as stated above).
[0086] In addition, as the substituents on the spiro cyclo lower alkyl groups, there may be mentioned, for example,
a lower alkyl group, a lower alkoxy group, a hydroxy lower alkyl group, an aryl group, and so on, and, among them, a
lower alkyl group and a lower alkoxy group, and so on, are more preferable.

15 [0087] Said saturated or unsaturated five- to eight-membered rings may be further fused with any of a cyclic lower
alkyl group, a heteroaromatic ring group selected from a set of groups of an aryl group, an imidazolyl group, an isoxazolyl
group, an isoquinolyl group, an isoindolyl group, an indazolyl group, an indolyl group, an indolydinyl group, an isothi-
azolyl group, an ethylenedioxyphenyl group, an oxazolyl group, a pyridyl group, a pyradinyl group, a pyrimidinyl group,
a pyridazinyl group, a pyrazolyl group, a quinoxalinyl group, a quinolyl group, a dihydroisoindolyl group, a dihydroindolyl

20 group, a thionaphthenyl group, a naphthyridinyl group, a phenazinyl group, a benzoimidazolyl group, a benzoxazolyl
group, a benzothiazolyl group, a benzotriazolyl group, a benzofuranyl group, athiazolyl group, a thiadiazolyl group, a
thienyl group, a pyrrolyl group, a furyl group, a furazanyl group, a triazolyl group, a benzodioxanyl group and a meth-
ylenedioxyphenyl group, or an aliphatic heterocyclic group(s) selected from an isoxazolinyl group, an isoxazolidinyl
group, a tetrahydropyridyl group, an imidazolidinyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a pip-

25 erazinyl group, a piperidinyl group, a pyrrolidinyl group, pyrrolinyl group, a morpholino group, a tetrahydroquinolinyl
group and a tetrahydroisoquinolinyl group.

[0088] Said fused rings may be substituted with one to three of the same or different substituents. As the specific
examples of such substituents, there may be mentioned the same ones as the substituents on Ar.
[0089] More preferably, R 2 and R 3 are each, common in all of (i), (ii) and (iii), the same or different and independently,
30 a hydrogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, or a substituent represented by the
formula Y 3a -W 2a -Y 4a -R sa (wherein: R sa , W 2a , Y 3a and Y 4a have the same meanings as stated above), or either R 2a or
R 3a forms, together with R 1a and X a . a saturated five- to eight-membered ring selected from sets of groups of (a-1)
and (b-1):

35

and

* — ' and O —

50 and the remaining one combines with a carbon atom or a nitrogen atom on said ring, and with a carbon atom, an
oxygen atom and/or a nitrogen atom on said ring-substituent to form a five- to seven-membered ring, or R 2 and R 3
work together to form a spiro cyclo lower alkyl group, or an oxo (keto, carbonyl) group together with Z to which they
bind, or form, together with Z a to which they bind, R 1a and X a , a saturated or an unsaturated five- to eight-membered
cyclic group which is selected from a set of groups of (a-1) and (a-2):

55

23

EP 1 1 99 306 A1

(a-1)

and

(a-2)

which may have one or more kinds of hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom,
and which may be substituted with one to three of the same or different substituent(s) selected from both a set of
groups of a lower alkyl group, a spiro cyclo lower alkyl group which may be substituted, a hydroxy group, a hydroxy
lower alkyl group, a lower alkoxy group, a lower alkyl group, a lower alkanoyloxy group, a hydroxy lower alkyl group,
a halo lower alkyl group, a carbamoyl lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower
alkoxycarbonylamino group, a lower alkoxycarbonylamino lower alkyl group, a lower alkylcarbamoyl group, a lower
alkylcarbamoyloxy group, a lower alkylamino group, a di-lower alkylamino group, an amino lower alkyl group, a lower
alkylamino lower alkyl group, a di-lower alkylamino lower alkyl group, a lower alkanoylamino group and an aroylamino
group, and a substituent represented by the formula Y 1a -W 1a -Y 2a -R pa (wherein: R pa , W 1a , Y 1a and Y 2a have the same
meanings as stated above), and further which may be fused with a ring selected from a cyclo lower alkyl group, an
aryl group, a hetero aromatic ring group selected from a pyridyl group and a pyrazolyl group or an aliphatic heterocyclic
group selected from a piperidinyl group and a pyrrolidinyl group, all of these cyclic groups may be substituted with one
to three of the same or different substituent(s) selected from the substituents mentioned above.
[0090] Among those cases, R 2b and R 3b are each, preferably, the same or different and independently, a hydrogen
atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group or a substituent represented by the formula Y 3b -W 2b -
Y 4b -R sb (wherein: R sb , W 2b , Y 3b and Y 4b have the same meanings as stated above), or either R 2b or R 3b forms, together
with R 1b and X b , a saturated five- to seven-membered cyclic group selected from a group of (b-1) and (b-2),

(b-i) <r~\ 0

H and

x — ' and u

and the remaining one of R 2b or R 3b forms a five- to seven membered ring by combining with a carbon atom or a
nitrogen atom on said ring, and with a carbon atom, an oxygen atom and/or a nitrogen atom in a ring-substituent on
said ring, or R 2b and R 3b work together to form a spiro cyclo lower alkyl group, or to form an oxo (keto, carbonyl) group
together with Z to which they bind, or they (R 2b and R 3b ) work together with Z b , R 1b and X b to form a saturated or an
unsaturated five- to seven-membered cyclic group selected from a set of groups of (b-1 ) and (b-2)

24

EP 1 199 306 A1

(b-1) (

o

and

o ■ o . & ana v

is which may have one or more kinds of hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom,
and which may be substituted with one to three of the same or different substituent(s) selected from both a set of
groups of a lower alkyl group, a spiro cyclo lower alkyl group which may be substituted, a hydroxy lower alkyl group
and a lower alkoxycarbonyl, and a set of groups represented by a formula Y 1b -W 1b -Y 2b -R pb (wherein: R pb , W 1b , Y 1b
and Y 2b have the same meanings as stated above), which may be fused with a ring selected from a set of groups of

20 a cyclic lower alkyl group, an aryl group and an aliphatic heterocyclic group selected from a group comprising a pipe-
ridinyl group and a pyrrolidinyl group, all of these cyclic groups may be substituted with one to three substituent(s)
selected from both a set of groups of a lower alkyl group, a spiro cyclo lower alkyl group, a hydroxy lower alkyl group
and a lower alkoxycarbonyl group, and a set of groups represented by the formula Y 1b -W 1b -Y 2b -R pb (wherein: R pb ,
W 1b , Y 1b and Y 2b have the same meanings as stated above).

25 [0091] R 4 and R 5 are each, the same or different, a hydrogen atom, a halogen atoms, a hydroxyl group, an amino
group ; or a substituent represented by the formula Y 3 -W 2 -Y 4 -R s (wherein: R s , W 2 , Y 3 and Y 4 have the same meanings
as stated above), or a lower alkyl group, an aryl group or an aralkyl group which may be substituted with one to three
of the same or different substituent(s) selected from both a set of groups consisting of a lower alkyl group, a cyano
group, a nitro group, a carboxyl group, a carbamoyl group, a formyl group, a lower alkanoyl group, a lower alkanoyloxy

30 group, a hydroxy lower alkyl group, a cyano lower alkyl group, a halo lower alkyl group, a carboxy lower alkyl group,
a carbamoyl lower alkyl group, lower alkoxy group, a lower alkoxycarbonyl group, lower alkoxycarbonylamino group,
a lower alkoxycarbonylamino lower alkyl group, a lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group, a
carbamoyloxy group, a lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, an amino group, a lower
alkylamino group, a di-lower alkylamino group, a tri-lower alkylammonio group, an amino lower alkyl group, a lower

35 alkylamino lower alkyl group, a di-lower alkylamino lower alkyl group, a tri-lower alkylammonio lower alkyl group, a
lower alkanoylamino group, an aroylamino group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group,
a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a hydroxyimino group and a lower alkoxyimino group
and a set of groups represented by the formula Y 3 -W 2 -Y 4 -R s (wherein: R s , W 2 , Y 3 and Y 4 have the same meanings
as stated above).

40 [0092] Here is a more detailed explanation about the forms of R 4 and R 5 . Thus, R 4 and R 5 are each a hydrogen
atom, halogen atoms, a hydroxy group, an amino group or a substituent represented by the formula Y 3 -W 2 -Y 4 -R s
(wherein: R s , W 2 , Y 3 and Y 4 have the same meanings as stated above), or a lower alkyl group, an aryl group or an
aralkyl group which may be substituted. Said lower alkyl group, aryl group and aralkyl group may be substituted with
one to three of the same or different substituent(s).

45 [0093] As specific examples of the substituents, there may be mentioned, for example, a substituent which may be
selected either from both a set of groups of a lower alkyl group, a cyano group, a nitro group, a carboxyl group, a
carbamoyl group, a formyl group, a lower alkanoyl group, a lower alkanoyloxy group, a hydroxy lower alkyl group, a
cyano lower alkyl group, a halo lower alkyl group, a carboxy lower alkyl group, a carbamoyl lower alkyl group, lower
alkoxy group, a lower alkoxycarbonyl group, lower alkoxycarbonylamino group, a lower alkoxycarbonylamino lower

so alkyl group, a lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group, a carbamoyloxy group, a lower alkylcar-
bamoyloxy group, di-lower alkylcarbamoyloxy group, an amino group, a lower alkylamino group, a di-lower alkylamino
group, a tri-lower alkylammonio group, an amino lower alkyl group, a lower alkylamino lower alkyl group, a di-lower
alkylamino lower alkyl group, a tri-lower alkylammonio lower alkyl group, a lower alkanoylamino group, an aroylamino
group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkyl-

55 sulfonylamino group, a hydroxyimino group and a lower alkoxyimino group and a set of groups represented by the
formula Y 3 -W 2 -Y 4 -R s (wherein: R s , W 2 , Y 3 and Y 4 have the same meanings as stated above).

[0094] The formula ^ is a single bond or a double bond, depending on the nature of the Z, R 1 , R 2 , R 3 and X, which
relate to the formulae.

25

EP 1 199 306 A1

[0095] What follows is the explanation about the compounds of the general formula (I) of the present invention

Formula ( I )

^k. 3 H

^HN % , (,)

o

«4 R L

[wherein: Ar, X, Y, Z, R 1; R 2 , R 3 , R 4 , R 5 and the formula ™ have the same meanings as stated above.]

[0096] Compounds of the general formula (I) have a good Cdk4 and/or Cdk6 inhibitory activity, and among them,

compounds of the general formula (l-a)

Y .X. H

HN T N ^r a <'- a )
O

[wherein: Ar a , X a , Y a , Z a , R 1a , R 2a , R 3a , R 4a , R 5a and the formula ™ have the same meanings as stated above.]
are more preferable, and especially the compounds of the general formula (l-b)

o

[wherein: Ar b , X b , Y b , Z b , R 1b , R 2b , R 3b , R^, R 5b and the formula ™ have the same meanings as stated above.] are
especially preferable.

[0097] Furthermore, the compounds represented by the general formula (l-p)

Ar p 0-P)

[wherein: Ar p is a nitrogen-containing heteroaromatic ring group which may be substituted; X p is a carbon atom (CH)
or a nitrogen atom; R 1p is a hydrogen or a lower alkyl group which may be substituted; R 2p is a hydrogen atom or an
oxo group (forms a carbonyl-group together with the carbon atom to which it binds), or forms, together with the carbon
atom to which it binds, R 1p and X p , a saturated or an unsaturated five- or six-membered cyclic group which may contain
one or more kinds of hetero atom(s) selected from a group of a nitrogen atom and a sulfur atom, which may be sub-
stituted; R 4p and R 5p are each, the same or different, a hydrogen atom, halogen atoms, a hydroxy group, an amino

26

EP 1 199 306 A1

group and a lower alkyl group, an aryl group, or an aralkyl group which may be substituted]
are included in the compounds of general formula (I) and show a good Cdk4 and/or Cdk6 inhibitory activity.
[0098] A further explanation about the compounds of the general formula (l-p) is as follows. Ar p is, for example, a
nitrogen-containing heteroaromatic ring group selected from a set of groups of a pyridyl group, a pyrimidinyl group, a
pyradinyl group, a pyridazinyl group, athiazolyl group, an isothiazolyl group, an oxazolyl group, an isoxazolyl group,
a pyrazolyl group, a pyrrolyl group, an imidazolyl group, an indolyl group, an isoindolyl group, a quinolyl group, an
isoquinolyl group, a benzothiazolyl group and a benzoxazolyl group, and, among them, for example, a nitrogen-con-
taining heteroaromatic ring group selected from a set of groups of a pyridyl group, a pyrimidinyl group, pyrazinyl group,
a pyridazinyl group, a thiazolyl group, a pyrazolyl group and an imidazolyl group is more preferable, and a nitrogen-
containing heteroaromatic ring group selected from a set of groups of, for example, a pyridyl group and a pyrazolyl
group is especially preferable.

[0099] As specific examples of the saturated or unsaturated five- or six-membered cyclic groups which R 2b forms,
together with the carbon atom to which it bind, R 1b and X p , there may be mentioned those in (a) or in (b). and so on.

(a)

O O

or

(to

& ■ O • (!>•(!)

or

[0100] Among the compounds of the general formula (l-p), preferable compounds are, for example, those which are
optionally substituted on Ar p or on the saturated or unsaturated five- or six-membered cyclic groups which forms to-
gether with the carbon atom binding to R 2p , R-| P and X p , with one to three substituent(s) selected from either a set of
groups consisting of a lower alkyl group, a hydroxyl group, a cyano group, halogen atoms, a nitro group, a carboxyl
group, a carbamoyl group, a formyl group, a lower alkanoyl group, a hydroxy lower alkyl group, a cyano lower alkyl
group, a halo lower alkyl group, a carboxy lower alkyl group, a carbamoyl lower alkyl group, lower alkoxy group, a
lower alkoxycarbonyl group, a lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group, a carbamoyloxy group, a
lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, an amino group, a lower alkylamino group, a di-
lower alkylamino group, a tri-lower alkylammonio group, an amino lower alkyl group, a lower alkylamino lower alkyl
group, a di-lower alkylamino lower alkyl group, a tri-lower alkylammonio lower alkyl group, a lower alkanoylamino group,
an aroylamino group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfonylamino group, a hydroxyimino
group and a lower alkoxyimino group, or those represented by a formula Y 1p -W-Y 2p -R pp [wherein: R pp is a hydrogen
atom or a lower alkyl group, a cyclo lower alkyl group, a lower alkenyl group, a lower alkynyl group, an aryl group, a
heteroaromatic ring group or an aliphatic heterocyclic group, each of which may be substituted; W is a single bond, an
oxygen atom, a sulfur atom, asulfinyl group, asulfonyl group, NR qp . S0 2 NR qp , N(R qp )S0 2 NR rp , N(R qp )S0 2 , CH(OR qp ),
CONR qp , N(R qp )CO, N(R qp )CONR rp , N(R qp )COO, N(R qp )CSO, N(R qp )COS, C(R qp )=CR rp , C=-C, CO, CS, OC(O), OC
(0)NR qp , OC(S)NR qp , SC(O), SC(0)NR qp or C(0)0 (wherein: R qp and R^ are each a hydrogen, a lower alkyl group,
an aryl group or an aralkyl group which may be substituted); Y 1p and Y 2p are each, the same or different, a single bond
or a straight-chain or branched lower alkylene group],
[0101] Furthermore, in the compounds of the general formula (I):

27

EP 1 199 306 A1

(i)

10 [wherein: Ar, X, Y, Z, R.|, R 2 , R 3 , R 4 , R 5 and the formula ™ have the same meanings as stated above.]

substitution with R 4 , R 5 and -HNCONH-Ar may occur at any positions of the benzene ring. Therefore, the compounds
of the general formula (I) are composite of the compounds of the general formula (1-1 ),

20

[wherein: Ar, X, Y, Z, R 1; R 2 , R 3 , R 4 , R 5 and the formula -~ have the same meanings as stated above.]
and the compounds of the general formula (I-2)

25

30

O

[wherein: Ar, X, Y, Z, R 1s R 2 , R 3 , R 4 , R 5 and the formula ™ have the same meanings as stated above.]
and the compounds of the general formula (I-3),

40

45

50

(I-3)

[wherein: Ar, X, Y, Z, R 1s R 2 , R 3 , R 4 , R 5 and the formula ™ have the same meanings as stated above.]
and the compounds of the general formula (I-4).

55

28

EP 1 199 306 A1

d-4)

10

[wherein: Ar, X, Y, Z, R 1; R 2 , R 3 , R 4 , R 5 and the formula ™ have the same meanings as stated above.].

Among these compounds, the compounds of the general formula (l-l) are the most preferable.

[01 02] As the pharmaceutical^ acceptable salts of the compounds of the general formula (I), there may be mentioned

those ordinally ones usually acceptable as medicines, namely, salts of the carboxyl group which may exist as the ring-

*s substituent, and those of the basic or acidic residue(s) in the side chain(s).

[01 03] As the basic additive salt of said carboxyl group or other acidic residue, there may be mentioned , for example,
in addition to the alkali metal salts such as, for example, a sodium salt or potassium salt; the alkaline earth metal salts,
such as calcium salt and magnesium salt, the ammonium salts, such as trimethylamine salt, triethylamine salt; aliphatic
amine salts, such as dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, procaine

20 salt, and so on; aralkylamine salts, such as dibenzylethylenediamine salt, and so on; herero aromatic amine salt, such
as pyridine sale, picoline salt, quinoline salt, isoquinoline salt, and so on; the quaternary ammonium salts, such as
tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt,
benzyltributylammonium salts, methyltrioctylammonium salt, tetrabutylammonium salt, and so on; the basic aminoacid
salts, such as arginine salt and lysine salt, and so on.

25 [0104] As acid additive salt of the basic group(s) on the side chain(s), there may be mentioned, for example, the
inorganic salts, such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate, and so on; the
organic salts, such as acetate, propionate, lactate, maleate, fumarate, tartrate, malate, citrate, ascorbate, and so on;
the sulfonic acid salts, such as methanesulfonate, isethionic acid salt, benzenesulfonate, toluenesulfonate, and so on;
the acidic aminoacid salts, such as aspartate, glutamate, and so on.

30 [0105] As pharmaceutical^ acceptable nontoxic esters of the compounds of the general formula (I), there may be
mentioned ordinally esters of said carboxyl group.

[0106] What follows are the examples of the most preferable compounds among the compounds of the general
formula (I) of the present invention. Those are, in addition to the compounds in the Examples described below, N'-(pyr-
rolidino[2,1 -b]isoindolin-4-on-8-yl)-N-(5-(2-octylaminomethyl)pyrazol-3-yl)urea (compound 563), N'-(pyrrolidino[2,1 -b]

35 isoindolin-4-on-8-yl)-N-(5-(2-methyl-4,4-dimethylpentylaminomethyl)pyrazol-3-yl)urea (compound 564), N'-(pyrrolidi-
no[2,1-b]isoindolin-4-on-8-yl)-N-(5-(2-methoxyindan-2-ylaminomethyl)pyrazol-3-yl)urea (compound 581),
N'-(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)-N-(5-(2-methylindan-2-ylaminomethyl)pyrazol-3-yl)urea (compound 589),
N'-(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)-N-(5-(5-chloroindan-2-ylaminomethyl)pyrazol-3-yl)urea (compound 595),
N'-(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)-N-(5-(6-methylpyridin-2-yl)pyrazol-3-yl)urea (compound 605), N'-(pyrrolidino

40 [2,1 -b]isoindolin-4-on-8-yl)-N-(5-(pyrrolidin-2-yl)pyrazol-3-yl)urea (compound 611), N'-(pyrrolidino[2,1 -b]isoindolin-
4-on-8-yl)-N-(5-(t-butylaminomethyl)pyrazol-3-yl)urea (compound 662), N'-(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)
-N-(5-(pyrazolo[5,4-b]pyridin-3-yl)urea(compound613),N l -(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)-N-(5-(1 -hydroxymeth-
ylcyclopentylaminomethyl)pyrazol-3-yl)urea (compound 572), N'-(pyrrolidino[2,1-b]-4-oxoisoindolin-8-yl)-N-(5-(N-t-
butyl-N-methyl-aminomethyl)pyrazol-3-yl)urea (compound 596), N'-(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)-N-(4-(N-

45 benzyl-1 ,2,5,6-tetrahydropyridin-4-yl)pyridin-2-yl)urea (compound 254), N'-(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)
-N-(4-(N-benzyl-4-piperidyl)pyridin-2-yl)urea (compound 255), N'-(pyrrolidino[2,1-b]isoindolin-4-on-8-yl)-N-(4-(N-ben-
zyl-1 ,2,5,6-tetrahydropyridin-3-yl)pyridin-2-yl)urea (compound 256), N'-(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)
-N-(4-(N-benzyl-3-piperidyl)pyridin-2-yl)urea (compound 257), N'-(pyrrolidino[2,1 -b]-4-oxoisoindolin-8-yl)
-N-(4-(1 ,2.5,6-tetrahydropyridin-3-yl)pyridin-2-yl)urea, N'-(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)-N-(4-(N-acetyl-3-pip-

50 eridyl)pyridin-2-yl)urea, IST- (pyrrol id ino[2,1 -b]isoindolin-4-on-8-yl)-N-(piperidino[-3,4-c]pyridin-5-yl)urea (compound
317), N'-(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)-N-(pyrrolidino[3,4-c]pyridin-5-yl)urea, N'-(pyrrolidino[2,1 -b]isoindolin-
4-on-8-yl)-N-(4-(cyclohexylaminoethyl)pyridin-2-yl)urea. N'-(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)-N-(4-(N-cyclohexy-
lpyrrolidin-3-yl)pyridin-2-yl)urea (compound 1 80), N'-(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)-N-(4-(N-benzylpyrrolidin-
3-yl)pyridin-2-yl)urea (compound 165), N'-(N-cyclopentyl-3-methylisoindolin-1 -on-4-yl)-N-(pyridin-2-yl)urea (com-

55 pound 428). N'-(3-t-butylisoindolino[3,2-b]oxazolidin-4-on-8-yl)-N-(4-(N-benzylpyrrolidin-3-yl)pyridin-2-yl)urea (com-
pound 526), N'-(2-methylisoindolino[3,2-b]perhydro-1 ,3-oxazin-5-on-9-yl)-N-(4-(N-benzylpyrrolidin-3-yl)pyridin-2-yl)
urea (compound 541), and N'-(isoindolino[2,3-b]perhydro-1 ,4-methano-6,11a-benzoxazin-11-on-7-yl)-N-(pyridin-2-yl)
urea (compound 476), and so on.

29

EP 1 199 306 A1

Among them, those compounds which follow, for example, are especially preferable.

N'-(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)-N-(5-(2-octylaminomethyl)pyrazol-3-yl)urea, N'-(pyrrolidino[2,1 -b]isoindolin-
4-on-8-yl)-N-(5-(2-methyl-4,4-dimethylpentylaminomethyl)pyrazol-3-yl)urea, N'-(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)
-N-(5-(2-methoxyindan-2-ylaminomethyl)pyrazol-3^

dan-2-ylaminomethyl)pyrazol-3-yl)urea, N'-(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)-N-(5-(5-chloroindan-2-ylaminome-
thyl)pyrazol-3-yl)urea, N'-(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)-N-(4-(N-benzyl-1 ,2,5,6-tetrahydropyridin-4-yl)pyridin-
2-yl)urea, N'-(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)-N-(4-(N-benzyl-4-piperidyl)pyridin-2-yl)urea, N'-(pyrrolidino[2,1 -b]
isoindolin-4-on-8-yl)-N-(4-(N-benzyl-N'-(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)-N-(piperidino[3,4-c]pyridin-5-yl)urea,
N'-(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)-N-(4-(N-cyclohexylpyrrolidin-3 -yl)pyridin-2-yl)urea, N'-(pyrrolidino[2.1 -b]iso-
indolin-4-on-8-yl)-N-(4-(N-benzylpyrrolidin-3-yl)pyridin-2-yl)urea, N'-(3-t-butylisoindolino[3,2-b]oxazolidin-4-on-8-yl)
-N-(4-(N-benzylpyrrolidin-3-yl)pyridin-2-yl)urea, N'-(2-methylisoindolino[3,2-b]perhydro-1 ,3-oxazin-5-on-9-yl)-N-(4-
(N-benzylpyrrolidin-3-yl)pyridin-2-yl)urea, and N'-(isoindolino[2,3-b]perhydro-1 ,4-methano-6, 1 1 a-benzoxazin-11 -on-
7-yl)-N-(pyridin-2-yl)urea, and so on.

Preparation methods of the compound of formula (I)

[0107] Next, the preparation methods of the compound of formula (I) of the present invention are illustrated.
[0108] The compound of the general formula (I) can be prepared by the following preparation method A. B and C,
respectively.

Preparation method A

[0109] The compound of formula (I) can be prepared by reacting the compound of formula (III)

[in the formula, X and Z independently represent carbon atom or nitrogen atom, or, if appropriate, form CH or nitrogen,
together with R 10 or R 20 and/or R 30 to which they bind, Y is CO, SO or S0 2 , Ri 0 is

(1) hydrogen or

(2) a substituent represented by Y3o- w 2o _Y 4o _R so

(wherein, R s0 is hydrogen or lower alkyl group, lower alkenyl group, lower alkynyl group, cyclo-lower alkyl group,
aryl group, heteroaromatic ring group selected form the group consisting of imidazolyl group, isoxazolyl group,
isoquinolyl group, isoindolyl group, indanzolyl group, indolyl group, indolizinyl group, isothiazolyl group, ethylene-
dioxophenyl group, oxazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl
group, quinoxalinyl group, quinolyl group, dihydroisoindolyl group, dihydroindolyl group, thionaphthyl group, naph-
thidinyl group, phenazinyl group, benzoimidazolyl group, benzoxazolyl group, benzothiazolyl group, benzotriazolyl
group, benzofuranyl group, thiazolyl group, thiadiazolyl group, thienyl group, pyrrolinyl group, furyl group, furazanyl
group, triazolyl group,

benzodioxanyl group and methylenedioxyphenyl group, or aliphatic heterocyclic group selected form the group
consisting of isoxazolyl group, isoxazolidinyl group, tetrahydropyridyl group, imidazoldinyl group, tetrahydrofuryl
group, piperazinyl group, piperidinyl group, pyrrolidinyl -group, pyrrolinyl group, morpholino group, tetrahydroqui-
nolyl group and tetrahydroisoquinolyl group,
each of which may have 1 to 3 substituents,
W 20 is a single bond, oxygen, sulfur,

SO, S0 2 , NR t0 , SO 2 NR t0 , N(R t0 )SO 2 NR u0 , N(R t0 )SO 2 , CH(OR t0 ), CONR t0 , N(R t0 )CO, N(R t0 )CONR u0 , N(R t0 )COO,
N(R t0 )CSO, N(R t0 )COS, C(R v0 )=CR r0 , C=C, CO ; CS, OC(O), OC(O)NR t0 , OC(S)NR t0 , SC(O), SC(O)NR t0 or C
(O)O(wherein, R t0 and R u0 are

(i) hydrogen or

(ii) a substituent selected from the group consisting of lower alkyl group, optionally protected hydroxyl group,

30

EP 1 199 306 A1

cyano, halogen atom, nitro group, carboxyl group which may be protected, carbamoyl group, formyl group,
lower alkynoyl group, lower alkynoyloxy group, optionally protected hydroxyl lower alkyl group, cyano lower
alkyl group, halogenated lower alkyl group, optionally protected carboxyl lower alkyl group, carbamoyl lower
alkyl group, lower alkoxy group, lower alkoxycarbonyl group, lower alkoxycarbonylamino group, lower alkox-
ycarbonylamino-lower alkyl group, lower alky Icarbamoyl group, di- lower alkylcarbamoyl group, carbamoyloxy
group, lower

alkylcarbamoyloxy group,

di-lower alkylcarbamoyloxy group, optionally protected amino group, lower alkylamino group, di-lower
alkylamino group, tri-lower alkylammonio, optionally protected amino lower alkyl group, lower alkyl amino-
lower alkyl group, di-lower alkyl amino-lower alkyl group, tri-lower alkyl amino-lower alkyl group, lower al-
kanoylamino group, aroylamino group, lower alknoylammonio-lower alkyl group, lower alkylsulf inyl group, low-
er alkylsulfonyl group, lower alkylsulfonylamino group, optionally protected hydroxyimino and lower alkoxy-
imino group or

(iii)lower alkyl group, aryl group or aralkyl group, each of which may have 1 to 3 substituents defined above
in (ii)),

Y 30 and Y 40 are independently single bond or straight-chain or branched lower alkylene),

(3) lower alkyl group, which may have independently 1 to 3 substituents selected from the group (A)consisting of
lower alkyl group, optionally protected hydroxyl group group, cyano group, halogen atom, nitro group, carboxyl
group which may be protected, carbamoyl group, formyl group, lower alkynoyl group, lower alkynoyloxy group,
optionally protected hydroxyl lower alkyl group, cyano lower alkyl group, halogenated lower alkyl group, optionally
protected carboxyl lower alkyl group, carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group,
lower alkoxycarbonylamino group, lower alkoxycarbonylamino-lower alkyl, lower alkylcarbamoyl, di-lower alkyl-
carbamoyl, carbamoyloxy group, lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, optionally pro-
tected amino group, lower alkyl amino group, di-lower alkyl amino group, tri-lower alkylammonio group, amino
lower alkyl group, lower alkyl amino-lower alkyl group, di-lower alkyl amino-lower alkyl group, tri-lower alkyl amino-
lower alkyl group, lower alknoylamino group, aroylamino group, lower alknoylammonio-lower alkyl group, lower
alkylsulfinyl group, lower alkylsulfonyl group, lower alkylsulfonylamino group, optionally protected hydroxyimino
and lower alkoxyimino group,

and the group (B) represented by the formula of Y 30 -W 20 -Y 40 -R s0 (wherein, R s0 , W 20 , Y 30 and Y 40 have the same
meanings as described above), or R 10 is taken together with X to form nitrogen atom,

R 20 and R 30 are, the same or different, independently hydrogen or optionally protected hydroxyl group, lower alkyl
group, lower alkoxy or the substituent represented by the formula of Y 30 -W 2 o-Y4o-R s o (wherein, R s0 , W 20 , Y 30 and
Y 40 have the same meanings as described above),

either R 20 or R 30 is taken together with R 10 and X to form saturated five to eight-membered rings selected from
the group consisting of

and

(b) r Ns > c N > N ' N >

\ / > > — ' > Q—J and

and the other may form the five- to seven-membered rings by binding to the carbon atom or nitrogen atom of the
ring, the carbon atom, oxygen atom and/or nitrogen atom in the substituent of the ring,

31

EP 1 199 306 A1

or R 2 o and R 30 are taken together to form spirocyclic lower alkyl, oxo group together with Z to which they bind, or
R 20 and R 30 form together Z, R-| , X, to which they bind or saturated or unsaturated five- to eight-membered rings
selected from sets of the groups of (a) and (b):

and

9

, which may contain one or more kinds of hetero atom(s) selected from a group of a nitrogen atom, an oxygen
atom and a sulfur atom, and which may be fused with the group selected from

(i) cyclo-lower alkyl group,

(ii) aryl group,

(iii) heteroaromatic ring group selected from the group consisting of imidazolyl group, isoxazolyl group, isoqui-
nolyl group, isoindolyl group, indanzolyl group, indolyl group, indolizinyl group, isothiazolyl group, ethylenedi-
oxophenyl group, oxazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl
group, quinoxalinyl group, quinolyl group, dihydroisoindolyl group, dihydroindolyl group, thionaphthyl group,
naphthidinyl group, phenazinyl group, benzoimidazolyl group, benzoxazolyl group, benzothiazolyl group, ben-
zotriazolyl group, benzofuranyl group, thiazolyl group, thiadiazolyl group, thienyl group, pyrrolinyl group, furyl
group, furazanyl group, triazolyl group, benzodioxanyl group and methylenedioxyphenyl group, or (iv)aliphatic
heterocyclic group selected from the group consisting of isoxazolyl group, isoxazolidinyl group, tetrahydropy-
ridyl group, imidazoldinyl group, tetrahydrofuryl group, piperazinyl group, piperidinyl group, pyrrolidinyl group,
pyrrolinyl group, morpholino group, tetrahydroquinolyl group and tetrahydroisoquinolyl group,

ich may have the same or diffent 1 to 3 substituent(s) selected from

(1)a substituent selected from the group consisting of lower alkyl, optionally substituted spirocyclic lower alkyl,
optionally protected hydroxyl group, cyano, halogen atom, nitro, carboxyl group which maybe protected, carbamoyl
group, formyl group, lower alkynoyl group, lower alkynoyloxy group, optionally protected hydroxyl lower alkyl group,
cyano lower alkyl group, halogenated lower alkyl group, optionally protected carboxyl lower alkyl group, carbamoyl
lower alkyl group, lower a Ikoxy group, lower alkoxycarbonyl group, lower alkoxycarbonylamino group, lower alkox-
ycarbonylamino-lower alkyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, carbamoyloxy
group, lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, optionally protected amino group, lower
alkyl amino group, di-lower alkylamino group, tri-lower alkylammonio group, optionally protected amino lower alkyl
group, lower alkylamino-lower alkyl group, di-lower alkylamino-lower alkyl group, tri-lower alkylamino-lower alkyl
group, lower alknoylamino group, aroylamino group, lower alknoylammonio-lower alkyl group, lower alkylsulfinyl
group, lower alkylsulfonyl group, lower alkylsulfonylamino group, optionally protected hydroxyimino group and
lower alkoxyimino group,

32

EP 1 199 306 A1

and (2)the group represented by formula of Y 10 -W 10 -Y 20 -R p0 (wherein, R p0 is hydrogen atom or lower alkyl, lower
alkenyl, or lower alkynyl, each of which may have 1 to 3 of said substituents, or

(i) cyclo-lower alkyl group,

(ii) aryl group,

(iii) heteroaromatic ring group selected form the group consisting of imidazolyl group, isoxazolyl group, isoqui-
nolyl group, isoindolyl group, indanzolyl group, indolyl group, indolizinyl group, isothiazolyl group, ethylenedi-
oxophenyl group, oxazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl
group, quinoxalinyl group, quinolyl group, dihydroisoindolyl group, dihydroindolyl group, thionaphthyl group,
naphthidinyl group, phenazinyl group, benzoimidazolyl group, benzoxazolyl group, benzothiazolyl group, ben-
zotriazolyl group, benzofuranyl group, thiazolyl group, thiadiazolyl group, thienyl group, pyrrolinyl group, furyl
group, furazanyl group, triazolyl group, benzodioxanyl group and methylenedioxyphenyl group, or

(iv) aliphatic heterocyclic group selected form the group consisting of isoxazolyl group, isoxazolidinyl group,
tetrahydropyridyl group , imidazolidinyl group, tetrahydrofuryl group, piperazinyl group, piperidinyl group, pyr-
rolidinyl group, pyrrolinyl group, morpholino group, tetrahydroquinolyl group and tetrahydroisoquinolyl group,
each of which in (i) to (iv) may have bicyclic or tricyclic fused rings containing the partial structure selected from

, CJ? and ^— y

W 10 is single bond, oxygen, and sulfur,

SO, S0 2 , NR q0 , SO 2 NR q0 , N(R q0 )SO 2 NR r0 , N(R q0 )SO 2 , CH(OR q0 ), CONR q0 , N(R q0 )CO, N(R q0 )CONR r0 , N
(R q0 )COO, N(R q0 )CSO, N(R q0 )COS, C(R q0 )=CR r0 , C=C, CO, CS, OC(O), OC(O)NR q0 , OC(S)NR q0 , SC(O),
SC(O)NR q0 or C(0)0

(wherein, R q0 and R r0 are

(i) hydrogen or

(ii) a substituent selected from the group consisting of lower alkyl group, cyclo-lower alkyl group, optionally
protected hydroxyl group, cyano group, halogen atom, nitro, carboxyl group which may be protected, car-
bamoyl group, formyl group, lower alkynoyl group, lower alkynoyloxy group, optionally protected hydroxyl lower
alkyl group, cyano lower alkyl group, halogenated lower alkyl group ; optionally protected carboxyl lower alkyl
group, carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, lower alkoxycarbonylami-
no group, lower alkoxycarbonylamino-lower alkyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl
group, carbamoyloxy group, lower alkylcarbamoyloxy group,

di-lower alkylcarbamoyloxy group, optionally protected amino group, lower alkylamino group, di-lower
alkylamino group, tri-loweralkylammonio, optionally protected amino lower alkyl group, lower alkylamino-lower
alkyl group, di-lower alkylamino-lower alkyl group, tri-lower alkylammonio-lower alkyl group, lower alknoylami-
no group, aroylamino group, lower alknoylammonio-lower alkyl group, lower alkylsulfinyl group, lower alkyl-
sulfonyl group, lower alkylsulfonylamino group, optionally protected hydroxyimino and lower alkoxyimino
group, or (iii) lower alkyl group, aryl or aralkyl group, each of which may have 1 to 3 substituent described
above in (ii)) Y 10 and Y 20 independently represent single bond or straight-chain or branched lower alkyl group,
each of which may have one of said bicyclic ring or tricyclic ring), and moreover, a saturated or unsaturated
five- to eight-membered rings selected from the following group;

and

33

EP 1 1 99 306 A1

(b)

, which may be fused with the ring selected from the groups consisting of

(i) cyclo-lower alkyl group,

(ii) aryl group, or

(iii) heteroaromatic ring group selected form the group consisting of imidazolyl group, isoxazolyl group, isoqui-
nolyl group, isoindolyl group, indanzolyl group, indolyl group, indolizinyl group, isothiazolyl group, ethylenedi-
oxophenyl group, oxazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl
group, quinoxalinyl group, quinolyl group, dihydroisoindolyl group, dihydroindolyl group, thionaphthyl group,
naphthidinyl group, phenazinyl group, benzoimidazolyl group, benzoxazolyl group, benzothiazolyl group, ben-
zotriazolyl group, benzofuranyl group, thiazolyl group, thiadiazolyl group, thienyl group, pyrrolinyl group, furyl
group, furazanyl group, triazolyl group, benzodioxanyl group and methylenedioxyphenyl group, or

(iv) aliphatic heterocyclic group selected form the group consisting of isoxazolyl group, isoxazolidinyl group,
tetrahydropyridyl group , imidazolidinyl group, tetrahydrofuryl group, piperazinyl group, piperidinyl group, pyr-
rolidinyl group, pyrrolinyl group, morpholino group, tetrahydroquinolyl group and tetrahydroisoquinolyl group,
R 40 and R 50 are independently hydrogen, halogen atom, optionally protected hydroxyl group, optionally pro-
tected amino or the substituent represented by the formula of Y 30 -W 2 o-Y 40 -R s0 (wherein, R s0 , W 20 , Y 30 and
Y 40 have the same meanings as described above), or lower alkyl group, aryl group, or aralkyl group, each of
which may have the same or diffent 1 to 3 substituent(s) selected from the substituent group consisting of
lower alkyl group, cyano group, nitro group, carboxyl group which may be protected, carbamoyl group, formyl
group, lower alkynoyl group, lower alkynoyloxy group, optionally protected hydroxyl lower alkyl group, cyano
lower alkyl group, halogenated lower alkyl group, optionally protected carboxyl lower alkyl group, carbamoyl
lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, lower alkoxycarbonylamino group, lower
alkoxycarbonylamino-lower alkyl group, lower alkylcarbamoyl group, di- lower alkylcarbamoyl group, car-
bamoyloxy group, lower alkylcarbamoyloxy group, di-loweralkylcarbamoyloxy group, optionally protected ami-
no group, lower alkylamino group, di-lower alkylamino group, tri-lower alkylammonio group, optionally protect-
ed amino lower alkyl group, lower alkylamino-lower alkyl group, di-lower alkylamino-lower alkyl group, tri-lower
alkylammonio-lower alkyl group, lower alknoylamino, aroylamino group, lower alknoylammonio-lower alkyl
group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower alkylsulfonylamino group, optionally protected
hydroxyimino and lower alkoxyimino group, and the substituent group represented by the formula of Y 30 -W 20 -
Y 40 -R s o (wherein, R s0 . W 20 , Y 30 and Y 40 have the same meanings as described above), the formula — re P~
resents a single bond or double bond] with the compound of formula (IV)

[in the formula, A r0 is nitrogen containing heteroaromatic ring group selected from the group consisting of
pyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, thiazolyl group, isothiazolyl group, oxazolyl
group, isoxazolyl group, pyrazolyl group, pyrrolinyl group, imidazolyl group, indolyl group, isoindolyl group,
quinolyl group, isoquinolyl group, benzothiazolyl group and benzoxazolyl group:(1) heteroaromatic ring group,
which may have the same or diffent 1 to 3 substituent(s) selected from the substituents consisting of lower
alkyl group, optionally protected hydroxyl group, cyano group, halogen atom, nitro group, carboxyl group which
may be protected, carbamoyl group, formyl group, lower alkynoyl group, lower alkynoyloxy group, optionally
protected hydroxyl lower alkyl group, cyano lower alkyl group, halogenated lower alkyl group, optionally pro-
tected carboxyl lower alkyl group, carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl
group, lower alkoxycarbonylamino group, lower alkoxycarbonylamino-lower alkyl group, lower alkylcarbamoyl
group, di-lower alkylcarbamoyl group, carbamoyloxy group, lower alkylcarbamoyloxy group, di-lower alkylcar-
bamoyloxy group, optionally protected amino group, lower alkylamino group, di-lower alkylamino group, tri-
lower alkylammonio group, amino lower alkyl group, lower alkylamino-lower alkyl group, di-lower alkylamino-
lower alkyl group, tri-lower alkylammonio-lower alkyl group, lower alknoylamino group, aroylamino group, lower

O

(IV)

34

EP 1 199 306 A1

alknoylamidino-lower alkyl group, lower alkylsulf inyl group, lower alky Isulfony I group, lower alkylsu If onylamino
group, optionally protected hydroxyimino and lower alkoxyimino group, and the substituent represented by
the formula Y 10 -W 10 -Y 20 -R p0 (wherein, R p0 , W 10 , Y 10 and Y 20 have the same meanings as described above),

(2) which heteroaromatic ring group forms optionally protected 5 to 7 membered rings selected from

in which, the substituent (abbreviated as optionally protected substituent of the ring below) selected from the group
consisting of lower alkyl group, lower alkynoyl group, lower alkynoyloxy group, optionally protected hydroxyl lower
alkyl group, cyano lower alkyl group, halogenated lower alkyl group, optionally protected carboxyl lower alkyl group,
carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, lower alkoxycarbonylamino group,
lower alkoxycarbonylamino-lower alkyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, car-
bamoyloxy group, lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, lower alkylamino group, di-
lower alkylamino group, tri-loweralkylammonio group, optionally protected amino lower alkyl group, lower alkylami-
no-lower alkyl group, di-lower alkylamino-lower alkyl group, tri-lower alkylammonio-lower alkyl group, lower al-
knoylamino group, aroylamino group, lower alkylsulf inyl group, lower alkylsulfonyl group, lower alkylsulfonylamino
group, lower alknoylamidino-lower alkyl group,together with carbon atom of the ring, or the neighouring carbon
atom and carbon atom, oxygen atom and/or nitrogen atom in the optionally protected substituent of the ring, or
(3) which form optionally protected 5 to 7 membered rings selected from

in which, the substituent represented by formula :Y 10 -W 10 -Y 20 -R p0 (wherein, Y 10 , W 10 , Y 2 o and R p0 have the mean-
ings given above) is taken together with the carbon atom of the ring, and the neighouring carbon atom, carbon
atom, oxygen atom and/or nitrogen atom in said substituent]
to give the compound of formula (II)

R 40 R 50

[in the formula, wherein, Ar 0 , X, Y, Z, R 10 , R 2 o, FUo> ^50 anc ' tne formula ™ have the same meanings as
described above], followed by the elimination of appropriate pretective group to obtain the compound of formula (I)

35

EP 1 1 99 306 A1

R 3

R 5

HN

O

H

(I)

[in the formula,

Ar is nitrogen containing heteroaromatic ring group selected form the group consisting of pyridyl group, pyrimidinyl
group, pyrazinyl group, pyridazinyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group,
pyrazolyl group, pyrrolinyl group, imidazolyl group, indolyl group, isoindolyl group, quinolyl group, isoquinolyl group,
benzothiazolyl group and benzoxazolyl group,

(1) heteroaromatic ring group, which may have the same or different 1 to 3 substituent(s) selected from

(i) substituent consisting of lower alkyl group, hydroxyl group, cyano group, halogen atom, nitro group, carboxyl
group, carbamoyl group, formyl group, lower alkynoyl group, lower alkynoyloxy group, optionally protected
hydroxyl lower alkyl group, cyano lower alkyl group, halogenated lower alkyl group, carboxyl lower alkyl group,
carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, lower alkoxycarbonylamino
group, lower alkoxycarbonylamino-lower alkyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl
group, carbamoyloxy group, lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, amino group,
lower alkylamino group, di-lower alkylamino group, tri-lower alkylammonio group, amino lower alkyl group,
lower alkylamino-lower alkyl group, di-lower alkylamino-lower alkyl group, tri-lower alkylammonio-lower alkyl
group, lower alknoylamino group, aroylamino group, lower alknoylamidino-lower alkyl group, lower alkylsulfinyl
group, lower alkylsulfonyl group, lower alkylsulfonylamino group, hydroxyimino group and lower alkoxyimino
group, and

(ii) the substituent represented by formula Y-1-W-1-Y2-RP (in the formula, R p is hydrogen or lower alkyl, lower
alkenyl, or lower alkynyl. each of which may have 1 to 3 said substituents, or

(a) cyclo-lower alkyl group,

(b) aryl group,

(iii) heteroaromatic ring group selected from the group consisting of imidazolyl group, isoxazolyl group, isoqui-
nolyl group, isoindolyl group, indanzolyl group, indolyl group, indolizinyl group, isothiazolyl group, ethylenedi-
oxophenyl group, oxazolyl group, pyridyl group, pyrazinyl group, pyrimidiyl group, pyridazinyl group, pyrazolyl
group, quinoxalinyl group, quinolyl group, dihydroisoindolyl group, dihydroindolyl group, thionaphthyl group,
naphthidinyl group, phenazinyl group, benzoimidazolyl group, benzoxazolyl group, benzothiazolyl group, ben-
zotriazolyl group, benzofuranyl group, thiazolyl group, thiadiazolyl group, thienyl group, pyrrolinyl group, furyl
group, furazanyl group, triazolyl group, benzodioxanyl group and methylenedioxyphenyl group, or

(iv) aliphatic heterocyclic group selected form the group consisting of isoxazolinyl group, isoxazolidinyl group,
tetrahydropyridnyl group, imidazolidinyl group, tetrahydrofuryl group, tetrahydropyrayl group, piperazinyl
group, piperidinyl group, pyrrolidinyl group, pyrrolinyl group, morpholino group, tetrahydroquinolyl group and
tetrahydroisoquinolyl group,

each of which may contain bicyclic or tricyclic fused ring selected from the partial structure consisting of

and which may have 1 to 3 said substituents,
W 1 is single bond, oxygen atom, sulfur atom,

SO, S0 2 , NR q , S0 2 NR q , N(R q )S0 2 NR ri N(R q )S0 2 ,CH(OR q ), CONR qi N(R q )CO, N(R q )CONR r , N(R q )COO, N
(R q )CSO, N(R q )COS, C(R q )=CR ri C=C, CO, CS, OC(O), OC(0)NR qi OC(S)NR qi SC(O), SC(0)NR q or C(0)0

and

36

EP 1 199 306 A1

(wherein, R q and R r are

(i) hydrogen or

(ii) the substituent selected from the group consisting of lower alkyl group, cyclo-lower alkyl group, hydroxyl
group, cyano group, halogen atom, nitro group, carboxyl group, carbamoyl group, formyl group, lower alkynoyl
group, lower alkynoyloxy group, hydroxyl lower alkyl group, cyano lower alkyl group, halogenated lower alkyl
group, carboxyl lower alkyl group, carbamoyl lower alkyl group, lower alkoxy group, lower alkoxycarbonyl
group, lower alkoxycarbonylamino group, lower alkoxycarbonylamino-lower alkyl group, lower alkylcarbamoyl
group, di-lower alkylcarbamoyl group, carbamoyloxy group, lower alkylcarbamoyloxy group, di-lower alkylcar-
bamoyloxy group, amino, lower alkylamino group, di-lower alkylamino group, tri-lower alkylammonio group,
amino lower alkyl group ; lower alkylamino-lower alkyl group, di-lower alkylamino-lower alkyl group, tri-lower
alkylammonio-lower alkyl group, lower alknoylamino group, aroylamino group, lower alknoylamidino-lower
alkyl group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower alkylsulfonylamino group, hydroxyimino
and lower alkoxyimino group, or

(iii) lower alkyl, aryl or aralkyl, each of which may have 1 to 3 substituents given in (ii)).

Y 1 and Y 2 are independently single bond or straight-chain or branched lower alkylene, which may have one
of said bicyclic or tricyclic condesed ring),

(2) which heteroaromatic ring group
form 5 to 7 membered rings selected from

in which, the substituent (abbreviated as the substituent of the ring) selected from the group consisting of lower
alkyl group, lower alkynoyl group, lower alkynoyloxy group, hydroxyl lower alkyl group, cyano lower alkyl group,
halogenated lower alkyl group, carboxyl lower alkyl group, carbamoyl lower alkyl group, lower alkoxy group, lower
alkoxycarbonyl group, lower alkoxycarbonylamino group, lower alkoxycarbonylamino-lower alkyl group, lower
alkylcarbamoyl group, di-lower alkylcarbamoyl group, carbamoyloxy group, lower alkylcarbamoyloxy group, di-
lower alkylcarbamoyloxy group, lower alkylamino group, di-lower alkylamino group, tri-lower alkylammonio group,
amino lower alkyl group, lower alkylamino-lower alkyl group, di-lower alkylamino-lower alkyl group, tri-lower alky-
lammonio-lower alkyl group, lower alknoylamino group, aroylamino group, lower alkylsulfinyl group, lower alkyl-
sulfonyl group, lower alkylsulfonylamino and lower alkynoylamidino lower alkyl group,

together with carbon atom of the ring, the substutent or the neighouring carbon atom and carbon atom, oxygen
atom and/or nitrogen atom in the substituent of the ring, or
(3) which heteroaromatic ring group
forms 5 to 7 membered rings selected from

and

37

EP 1 199 306 A1

0..O -O

the substituent represented by formula Y-rWi-Y 2 -R p (in the formula. Y-| , W-| , Y 2 and R p have the same meanings
given above) together with carbon atom of the ring, or the neighouring carbon atom, carbon atom ; oxygen atom
and/or nitrogen atom in said substituent,
10 R 1 is

(1) hydrogen or

(2) the substituent represented by formula Y 3 -W 2 -Y 4 -R s (in the formula, R s is

*s (i)hydrogen or

(ii) lower alkyl group, lower alkenyl group, lower alkynyl group, cyclo-lower alkyl group, aryl group,

(iii) heteroaromatic ring group selected form the group consisting of imidazolyl group, isoxazolyl group, iso-
quinolyl group, isoindolyl group, indanzolyl group, indolyl group, indolizinyl group, isothiazolyl group, ethylen-
edioxophenyl group, oxazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, pyra-

20 zolyl group, quinoxaliyl group, quinolyl group, dihydroisoindolyl group, dihydroindolyl group, thionaphthyl

group, naphtidinyl group, phenazinyl group, benzoimidazolyl group, benzoxazolyl group, benzothiazolyl group,
benzotriazolyl group, benzofuranyl group, thiazolyl group, thiadiazolyl group, thienyl group, pyrrolinyl group,
fury I group, furazanyl group, triazolyl group, benzodioxanyl group and methylenedioxyphenyl group, or

(iv) aliphatic heterocyclic group selected form the group consisting of isoxazolyl group, isoxazolidinyl group,
25 tetrahydropyridyl group, imidazolidinyl group, tetrahydrofuryl group, piperazinyl group, piperidinyl group, pyr-

rolidinyl group, pyrrolinyl group, morpholino group, tetrahydroquinolyl group and tetrahydroisoxaquinolyl
group, each of which in (ii) to (iv) may have 1 to 3 said substituents,

W 2 is single bond , oxygen, sulfur, SO, S0 2 , NR t , S0 2 NR t , N(R t )S0 2 NR u , N(R t )S0 2 , CH(OR t ), CONR t , N(R t )CO,
30 N(R t )CONR u , N(R t )COO, N(Rt)CSO, N(R t )COS, C(R v )=CR r , C=C, CO, CS, OC(O), OC(0)NR t , OC(S)NR t , SC

(O), SC(0)NR t orC(0)0
(wherein, R t and R u are

(i)hydrogen or

35 (ii)the substituent selected from

lower alkyl group, hydroxyl group, cyano group, halogen atom, nitro, carboxyl group, group carbamoyl group,
formyl group, lower alkynoyl group, lower alkynoyloxy group, hydroxyl lower alkyl group, cyano lower alkyl
group, halogenated lower alkyl group, carboxyl lower alkyl group, carbamoyl lower alkyl group, lower alkoxy
group, lower alkoxycarbonyl group, lower alkoxycarbonylamino group, lower alkoxycarbonylamino-lower alkyl

40 group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, carbamoyloxy group, lower alkylcarbamoy-

loxy group,

di-lower alkylcarbamoyloxy group, amino, lower alkylamino group, di-lower alkylamino group, tri-lower alky-

lammonio group, amino lower alkyl group, lower alkylamino-lower alkyl group, di-lower alkylamino-lower alkyl

group, tri-lower alkylammonio-lower alkyl group, lower alknoylamino group, aroylamino group, lower alknoyl-
45 amidino-lower alkyl group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower alkylsulfonylamino group,

hydroxyimino and lower alkoxyimino group, or

(iii)lower alkyl group, aryl or aralkyl group, each of which may

have 1 to 3 said substituents given in (ii)),

Y 3 and Y 4 are independently single bond or straight-chain
50 or branched lower alkylene group),

(3) lower alkyl group, which may have the same or diffent 1 to 3 substituent(s) selected from

(i) the substituent selected from
55 lower alkyl group, hydroxyl group, cyano group, halogen atom, nitro group, carboxyl group, carbamoyl group,

formyl group, lower alkynoyl group, lower alkynoyloxy group, hydroxyl lower alkyl group, cyano lower alkyl
group, halogenated lower alkyl group, carboxyl lower alkyl group, carbamoyl lower alkyl group, lower alkoxy
group, lower alkoxycarbonyl group, lower alkoxycarbonylamino group, lower alkoxycarbonylamino-lower alkyl

38

EP 1 199 306 A1

group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, carbamoyloxy group, lower alky Icarbamoy-
loxy group,

di-lower alkylcarbamoyloxy group, amino group, lower alkylamino group, di-lower alkylamino group, tri-lower
alkylammonio group, amino lower alkyl group, lower alkylamino-lower alkyl group, di-lower alkylamino-lower
alkyl group, tri-lower alkylammonio-lower alkyl group, lower alknoylamino group, aroylamino group, lower al-
knoylamidino-lower alkyl group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower alkylsulfonylamino
group, hydroxyimino and lower alkoxyimino group, and

(ii) the substituent represented by formula Y 3 -W 2 -Y 4 -R s (in the formula, R s , W 2 , Y 3 and Y 4 have the same

meanings given above),

or form nitrogen atom together with X,

R 2 and R 3 are independently hydrogen atom, hydroxyl group, lower alkyl group, lower alkoxy group or a sub-
stituent represented by the formula : Y 3 -W 2 -Y 4 -R s (in the formula, R s , W 2 , Y 3 and Y 4 have the same meanings
given above), or one of R 2 or R 3 forms, together with R-, and X, saturated 5 to 8 membered rings selected from

« O , O O •

and

w

the other of R 2 or R 3 forms 5 to 7 membered rings by taking together with the carbon atom or nitrogen-atom
of the ring, carbon atom, oxygen atom and/or nitrogen atom, each of which is comprised in the substituent of
the ring, or R 2 and R 3 are taken together with to form spiro lower alkyl, oxo together with Z, or form saturated
or unsaturated 5 to 8 membered rings selected from

and

39

EP 1 199 306 A1

, which may be fused together with the ring selected from

(1) cyclo-lower alkyl group, each of which may contain 1 or more hetero atoms selected from nitrogen atom, oxygen
atom and sulfur atom, which is taken together with binding Z,
5 (2) aryl group,

(3) heteroaromatic ring group selected from the group

consisting of imidazolyl group, isoxazolyl group, isoquinolyl group, isoindolyl group, indanzolyl group, indolyl group,
indolizinyl group, isothiazolyl group, ethylenedioxophenyl group, oxazolyl group, pyridyl group, pyrazinyl group,
pyrimidiyl group, pyridazinyl group, pyrazolyl group, quinoxalinyl group, quinolyl group, dihydroisoindolyl group,
10 dihydroindolyl group, thionaphthyl group, naphtidinyl group, phenazinyl group, benzoimidazolyl group, benzoxa-

zolyl group, benzothiazolyl group, benzotriazolyl group, benzofuranyl group, thiazolyl group, thiadiazolyl group,
thienyl group, pyrrolinyl group, furyl group, furazanyl group, triazolyl group, benzodioxanyl group and methylene-
dioxyphenyl group, or

(4) aliphalic heterocyclic group selected from the group consisting of isoxazolinyl group, isoxazolidinyl group, tet-
*5 rahydropyridyl group, imidazolidinyl group, tetrahydrofuryl group, tetrahydropyranyl group, piperazinyl group, pip-

eridinyl group, pyrrolidinyl group, pyrrolinyl group, morpholino group, tetrahydroquinolyl group and tetrahydroiso-
quinolyl group

each of which may have the same or diffent 1 to 3 substituent(s) selected from

20 (j)a substituent selected from the group consisting of lower alkyl, optionally substituted spirocyclo-lower alkyl

group, hydroxyl group, cyano group, halogen atom, nitro group, carboxyl group, carbamoyl group, formyl group,
lower alkynoyl group, lower alkynoyloxy group, hydroxyl lower alkyl group, cyano lower alkyl group, halogen-
ated lower alkyl group, carboxyl lower alkyl group, carbamoyl lower alkyl group, lower alkoxy group, lower
alkoxycarbonyl group, lower alkoxycarbonylamino group, lower alkoxycarbonylamino-lower alkyl group, lower

25 alkylcarbamoyl group, di-lower alkylcarbamoyl group, carbamoyloxy group, lower alkylcarbamoyloxy group,

di-lower alkylcarbamoyloxy group, amino, lower alkylamino group, di-lower alkylamino group, tri-lower alky-
lammonio group, amino lower alkyl group, lower alkylamino-lower alkyl group, di-lower alkylamino-lower alkyl
group, tri-lower alkylammonio-lower alkyl group, lower alknoylamino group, aroylamino group, lower alknoyl-
amidino-lower alkyl group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower alkylsulfonylamino group,

30 hydroxyimino and lower alkoxyimino group,

R 1 and X, and

(ii) a substituent represented by the formula: Y1-W-1-Y2-RP (in the formula, R p , W-| , Y 1 and Y 2 have the same
meanings given above),

35 R 4 and R 5 are same or independently hydrogen atom, halogen atom, hydroxyl. amino or the substituent represented

by formula: Y3-W 2 -Y 4 -R s (in the formula, R s , W 2 , Y 3 and Y 4 have the meanings given above), or lower alkyl, aryl
or aralkyl, each of which may have 1 to 3 substituents selected from

(i) the substituent selected from the group consisting of lower alkyl group, cyano group, nitro group, carboxyl
40 group, carbamoyl group, formyl group, lower alkynoyl group, lower alkynoyloxy group, hydroxyl lower alkyl

group, cyano lower alkyl group, halogenated lower alkyl group, carboxyl lower alkyl group, carbamoyl lower
alkyl group, lower alkoxy group, lower alkoxycarbonyl group, lower alkoxycarbonylamino group, lower alkox-
ycarbonylamino-lower alkyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, carbamoyloxy
group, lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, amino group, lower alkylamino
45 group, di-lower alkylamino group, tri-lower alkylammonio group, amino lower alkyl group, lower alkylamino-

lower alkyl group, di-lower alkylamino-lower alkyl group, tri-lower alkylammonio-lower alkyl group, lower al-
knoylamino group, aroylamino group, lower alknoylamidino-lower alkyl group, lower alkylsulfinyl group, lower
alkylsulfonyl group, lower alkylsulfonylamino group, hydroxyimino group and lower alkoxyimino group, and (ii)
the substituent represented by formual: Y 3 -W 2 -Y 4 -R s (in the formula, R s , W 2 , Y 3 and Y 4 have the same mean-
so ings given above),

X, Y, Z and the formula — have the same meanings given above].

[0110] The compound of the formula (I) can be prepared by subjecting the compound of the formula (III) to trichlo-
roacetylation or p-nitorphenoxycarbonylation followed by reacting with the compound of the formula (VI).
55 [0111] The reaction of the compound the formula (III) with the compound of the formula (IV) is usually carried out
using 1 moleof thecompoundtheformula (lll)togetherwith preferably about 1 mol of thecompound of theformula (IV).
[0112] In the reaction of trichloroacetylation or p-nitorphenoxycarbonylation of the compound of theformula (III), to
1 mole of the compound of the formula (III), the halogenated compound is used in usually 1 to 5 moles, preferably 1

40

EP 1 199 306 A1

mol. To 1 mole of the trichloroacetylated or p-nitrophenoxycarbonylated compound of the compound in formula (III),
the compound in formula (VI) is used in usually 1 to 5 mol, preferably 1 mol.

[01 13] The reaction may be carried out in the inactive solvents including the ether such as tetrahydrofuran, dioxane,
and the like, aromatic hydrocarbon such as benzene, toluene, and the like, or the mixture thereof.
[0114] The reaction temperature depends on the type of the starting material, usually between 0°C and the boiling
point of the solvent used, preferably, within the range from 20 to 100 °C.

[01 15] The reaction time is usually within the range from 20 minutes to 24 hours, preferably, from 1 to 4 hours, and
can be reduced or increased appropriately.

[0116] In the case of the compounds of the formula (III) and formula (IV), which contain functional group such as
hydroxyl, amino, carboxyl or the like or the substituent including such afunctional group, such as hydroxyl lower alkyl
group ; amino lower alkyl group, carboxyl lower alkyl group and the like, said hydroxyl group, amino group, carboxyl
group, hydroxyl lower alkyl group, amino lower alkyl group, carboxyl lower alkyl group and the like are preferably
protected by the appropriate protective group for hydroxyl, amino, carboxyl in advance. After the reaction, said protec-
tive group for the compound of the formula (II) is removed to obtain the compound of the formula (I).
[01 17] The protecting group of hydroxyl includes lower alkylsilyl such as tert-butyldimethylsilyl group, tert-butyldiphe-
nylsilyl group, and the like, lower alkoxymethyl such as methoxymethyl group, 2-methoxyethoxymethyl group, and the
like group, aralkyl such as benzyl group, p-methoxybenzyl group, and the like, acyl such as formyl group, acetyl group,
and the like. Preferably, tert-butyldimethylsilyl, acetyl and the like are used.

[0118] The amino-protecting group includes arylalkyl group such as benzyl group, p-nitrobenzyl group, and the like,
acyl such as formyl group, acetyl, and the like, lower alkoxycarbonyl group such as ethoxycarbonyl group, tert-butox-
ycarbonyl group, and the like, arylkyloxycarbonyl group such benzyloxycarbonyl group, p-nitorbenzyloxycarbonyl
group, and the like. Preferably, p-nitorbenzyl, tert-butoxycarbonyl group, benzyloxycarbonyl group and the like are used.
[0119] The carboxyl -protecting group includes tri-substituted silyl such as methyl, ethyl, tert-butyl and the like, ary-
lalkyl such as benzyl, p-methoxybenzyl and the like. Preferably, methyl, ethyl, benzyl and the like are used.
[0120] The method for removing the protecting group depends on the type and stability of the compound. Usually,
it is carried out according to the method disclosed in [Protective Groups in Organic Synthesis by T.W. Greene, published
by John Wiley & Sons Co. (1981)] or a similar method thereof. Specifically, it includes solvolysis using acid or base,
chemical reduction using metal hydride or catalytic hydrogenation using palladium carbon catalyst, Raney-nickle cat-
alyst.

[0121] One example of the compound of formula (I), which forms a bicyclic fused ring is illustrated as follows.
The compound of formula (I 1 )

(wherein, Ar, X, Y, R 1; Ft 4 and Ft 5 have the meanings given above), which is the compound in which R 2 and R 3 are
combined, together with Z, to form oxo radical, can be prepared by
reacting the compound represented by formula (IV)

(wherein Ar 0 has the meaning given above) with the compound represented by formula(IM')

41

EP 1 199 306 A1

NH 2

(in' )

(wherein X, Y, R 10 , R 40 and R 50 have the meaning given above) to afford the compound represented by formula (ll'-a)

(wherein, Ar 0 , X, Y, R 10 , R 40 and R 50 have the meaning given above) followed by the removal of the appropriate
protective group. The reaction condition of each steps follows the similar condition to the preparation method A.

Preparation method B

[0122] The compound of formula (I) can be prepared by reacting the compound represented by formula (V)

con 3 (V)

(wherein, X, Y, Z, R 10 , R 2 o, FUo> R 50 and tne formula ™ have the meanings given above) with the compound
represented by formula (VI)

H 2 N-Ar 0

(VI)

(wherein, Ar 0 has the meaning given above) to afford the compound represented by formula (II)

(wherein, Ar 0 , X, Y, Z, R 10 , R 20 , R 4o> R so and tne f° rmu l a ™ have the meanings given above) followed by the
removal of the appropriate protective group to afford the
compound represented by formula (I)

42

EP 1 199 306 A1

(wherein, Ar, X, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 and the formula ™ have the meanings given above).

[0123] Each step of said preparation method follows the method described in preparation method A for preparing
the compound of formula (I) and formula (II).

Preparation method C

[0124] This method illustrates the preparation of the compound represented by formula (I), in which Ar is pyrrazolyl
group. Reacting the compound represented by formula (VII)

o

T «> (VII)

(wherein, L is an optionally protected reactive group, which has the functional group converted to other functional
group ; T 10 is single bond or Ar 0 , which has the convertible functional group including straight-chain or branched lower
alkylene group, aryl group, heteroaromatic group, aliphatic heterocyclic group, or arylalkyl group, each of the above
group may be protected) with the compound represented by formula (VIII)

H 2 N-NH-R 60 (VIII)

(wherein, R 60 is hydrogen or the protective group of amino group) affords the compound represented by formula (IX)

(IX)

(wherein, T 10 , R 60 and L have the meanings given above), which is allowed to be reacted with the compound of formula
(III)

Y> NH 2 (III)

(wherein, X, Y, Z, R-) 0 , R 20 , R40, R50 ar| d the formula ™ have the meanings given above) and the reactive formic

43

EP 1 199 306 A1

ester derivative at the presence of desired base to afford the compound of formula (X)

(wherein, X, Y, Z, T 10 , R 10 , R 20 , R30, ^4o> ^50> tne formula ~- and L have the meanings given above) followed by
transformation of substituent L and/or the removal of the protective group to provide the compound of formula (I")

(wherein, T 1 is single bond or Ar, which has the convertible functional group including straight-chain or branched lower
alkylene group, aryl group, heteroaromatic, aliphatic heterocyclic, orarylalkyl group, Q represents W-|-Y2-Rp (wherein,
W 1; Y 2 and R p have the meanings given above), X, Y, Z, R 1; R 2 , R 3 , R 4 , R 5 and the formula --- have the meanings
given above).

[0125] In case of the preparation of the compound of formula (IX), which was prepared by the condensation of the
compound of formula (VII) andthecompound of formula (VIII), corresponding to 1 moleof thecompound of formula (VII),
1 or more mole, preferably, 2 to 3 moles of the compound of formula (VIII) is used. The reaction can be carried out in
the alcohol such as ethanol, butanol. In case where the compound of formula (VIII) form a salt with an acid,
the base such as triethylamine is preferably used in 2 to 5 moles, preferably 2 to 3 moles corresponding to 1 mole of
the compound of formula (VIII) to give the compound of formula (VIII) presence in free form.

[01 26] The reaction temperature is, usually between 20°C and the boiling point of the solvent used, preferably, within
the range from 50 °C to 1 50 °C.

[0127] The reaction time is usually within the range from 1 to 48 hours, preferably, from 2 to 24 hours.

[0128] In the reaction, where the compund of formula(X) is prepared by the reaction of the compound of formula

(IX) , the compound of formula (III) and the reactive formic ester derivative under the presence of an appropriate base,
1 mole or more, preferably, 1 to 3 mole of thecompound of formula (III) is used corresponding to 1 mole of thecompound
of formula (IX). 1 mole or more, preferably, 1 to 3 mole of the reactive formic ester derivative is used corresponding to
1 mole of the compound of formula (IX), and the base is used in 1 mole or more, preferably, 1 to 3 moles corresponding
to the reactive derivative of formic ester.

Said reactive formic ester derivative includes the compound, which may form amide carboxylic ester and is not limited
but represented by p-nitrophenyl chloro formate, methyl chloroformate.

[0129] The reaction is usually carried out in an inactive solvent. Said solvent includes haloalkane such as dichlo-

romethane, chloroform, ether such as ethylether, tetrahydrofuran, aromatic hydrocarbon such as benzene, toluene,

aprotic polar solvent such as dimethylformamide, acetone, ethyl acetate, or the mixed solvent thereof .

[01 30] The reaction temperature in the reaction of the compound of formula (IX) with reactive formic ester derivative,

is usually between 20 °C and the boiling point of the solvent used, preferably, within the range from 20 °C to 50 °C.

The reaction time is usually within the range from 30 minutes to 24 hours, preferably, from 1 to 24 hours. The reaction

temperature is, usually between 20 °C and the boiling point of the solvent used, preferably, within the range from 50

to 100 °C in the step reacting with the compound of formula (III) after the reaction has been completed.

[0131] The compound of formula (I") can be prepared by introducing a carboxyl group into the compound of formula

(X) using metal complex as a catalyst, followed by converting the compound to the amide, ester, and so on according

44

EP 1 199 306 A1

to the ordinary method and, if necessary, optional combination with the deprotecting of protective group for hydroxyl,
amino and carboxyl, and so on.

[0132] Alternatives to the preparation method using the compound of formula (IX), the compound of formula (III) and
reactive formic ester derivative, the compound of formula (X) can also be prepared by reacting the compound of formula
5 (III) with diphosgene in the presence of activated carbon to afford isocyanate, followed by the reaction with the com-
pound of formula (IX).

[0133] The reaction is usually carried out in an inactive solvent such as tetrahydrofuran.

[0134] The compound of formula (III) and diphosgene are used in a ratio of 1 :1 mole or more, preferably, 1:1. To 5
grams of activated carbon, the compound of formula (IX) is used in 1 or more moles, preferably 1 mole.
10 [0135] The reaction temperature is usually between 20 °C and the boiling point of the solvent used, preferably, within
the range from 30 °C to 1 00 °C.

[0136] The reaction time is usually from 30 minutes to 24 hours, preferably, within the range from 30 minute to 6 hours.
[01 37] To the process for converting the reactive substituent L, which has a functional group convertible to the other
functional group of the compound of formula (X), for instance, in a case where R represents an aromatic ring and L is
*s a halogen atom, the reaction of the compound of formula(X) with carbon monoxide using palladium as a catalyst in
the presence of phosphine ligand and base, in the alcohol solvent such as methanol and ethanol to afford the ester of
formula (X) followed by hydrolysis of the ester under the basic condition can be applied.

[0138] Said reactive substituent, which has afunctional group convertible to the other functional group includes for
example, hydroxyl, amino, carboxyl, ester, halogen atom.

20 [0139] In case of that the compound of formula (X) is used in 1 mole, palladium complex such as palladium acetate
and phosphine ligand such as 1 -bis(diphenylphosphino)ferrocene are each 5 to 50% by weight, preferably, 10 to 20
% by weight; and the base such as sodium hydrogen carbonate is 2 to 10 mole, preferably, 2 to 3 moles.
[0140] The reaction temperature is usually between 20 °C and the boiling point of the solvent used, preferably, within
the range from 50 to 100 °C. The reaction time is usually from 30 minutes to 24 hours, preferably, within the range

25 from 5 to 24 hours.

[0141] The method for further transforming the carboxylic acid prepared above can be carried out as similarly as the
method follows a method similar to the method for transforming the substituent of Ar described below.
[0142] After the completion of the reaction followed by routine method, the compound of formula (I") can be obtained,
if necessary, by deprotecting the protective group of hydroxyl, amino and carboxyl.
30 [0143] The deprotecting method of the protective group depends on the type of the protective group and the stability
of the desired compound and so on, and may follows the appropriate method described in literature mentioned above,
or a similar method there of.

[0144] Next, the transformation methods of the substituent on Ar of the compound of formula (I) are illustrated.
[0145] Ar may have various substituents as described above. For example, as described in the preparation method

35 a and B. the desired compound can be prepared by using the compound in which the desired sbustituent is introduced
into the starting material. However, for the purpose of improving the reactivity and yield and so on, for example, after
the preparation of the compound of formula(ll), which has -T-|-OR 7 (wherein, R 7 is the protective group of hydroxyl, T 1
has the meaning given above), various transforming reaction described in the transformation methods B to H methioned
below can be carried out for further transforming the functional group (Transformation method A) or protecting urea

40 moiety of the compound of formula (II) followed by introducing of the desired substituent.

Transformation method A

[0146] This method is a method for transforming the functional group on Ar without protecting the urea moiety. As
45 the various transformation methods, for example, as a starting material, the compound of formula (ll-c) was used;

50

55

(M-c)

[in the formula, Ar co represents Ar 0 given above, which comprises a substituent of -T-|-OR 7 (wherein, R 7 and T 1 have
the meanings given above), X, Y, Z, R 10 , R 20 , R30: R 4o> R so and tne formula ™ have the same meanings as given

45

EP 1 199 306 A1

above], to give the compound of formula (ll-d);

HN

O

H

(ll-d)

[in the formula, Ar d0 represents Ar 0 given above, which comprises a substituentof -T-| -OH (wherein, T 1 has the meaning
given above), X, Y, Z, R-| 0 , R 2 q, R3o> r 4o> r so and tne formula ™ have the saem meanings as given above] can be
prepared. And,for example, the compound of formula (ll-d) can be transformed to the compound of formula (ll-e);

[in theformula, Ar e0 represents Ar 0 given above, which comprises a substituent of -T-)-NH 2 (wherein, T-| has the meaning
given above), X, Y, Z, R 10 , R 2 o, R3o> ^Wo* R50 ar| d tne formula ™ have the meanings given above], according to the
well known synthetic method in organic synthetic chemistry for transforming alcohol to amine.

[0147] The deprotecting method of the protective group of hydroxyl group varies depending on the type of the pro-
tective group and the stability of the desired compound, and, if appropriate, may follows for example , the appropriate
method in the litelature described above or a similar method thereof.

[0148] The synthetic method for transforming alcohol to amine and the reaction condition are illustrated as follows.
For example, the Mitsunobu reaction using diethylazodicarboxylate, triphenylphosphine and phthalimide (or diazide
compoundphenylphosphate) can be used, or the method comprising the sulfonation using sulfonating agent such as
methanesulfonylchloride in the presence of base such as triethylamine followed by the reaction with phthalimide (or
sodium azide compound) and then treatment (or reduction) of the resulting compound with hydrazine is preferable.
[0149] The above reaction is usually carried out in an inactive solvent. Said solvent in Mitsunobu reaction, includes
for example, tetrahydrofuran, chloroform, dimethoxyethane, benzene, toluene and the like. In the reaction involved in
the sulfonation andtheamination using phthalimide (orsodium azide compound), the solvent such as dichloromethane,
chloroform, tetrahydrofuran, benzene, ethyl acetate, dimethylformamide can be used.

[0150] In the cleavage reaction of phthalimide using hydrazine, alcohols such as methanol and ethanol, in the re-
duction reaction of azide compound compound using hydrogenated metal complex, ether such as ethyl ether and
tetrehydrofuran, in the phosphine reduction using triphenylphosphine, tetrahydrofuran containing water, in the hydro-
genation reduction, alcohol such as methanol and ethanol are preferable respectively.

[0151] In the mitsunobu reaction, to 1 mole of the compound of formula (ll-d), diethylazodicarboxylate, triphenylphos-
phine and phthalimide (or diphenylphosphornylazide compound) are used in 1 mole or more, preferably, 1 to 5 mole,
respectively. In the reaction with phthalimide (orsodium azide compound) after sulfonation, to 1 mole of the compound
of formula (ll-d), the sulfonating agent is used in 1 mole or more, preferably, 1 to 3 mole. And the base used is 1 mole
or more, preferably, 1 to 3 mole corresponding to 1 mole of the sulfonating agent. In the next reaction with phthalimide
(or sodium azide compound), to 1 mole of the sulfonating reagent, phthalimide and a base or sodium azide compound
compound is used in 1 mole or more, preferably, 1 to 5 mole. In the cleavage reaction of a phthalimide group using
hydarzine : to 1 mole or more of the phthalimide compound, and the hydrazine is used in 1 mole or more, preferably,
1 to 1 0 mole. In the reduction of azide compound compund using hydrogenated metal complex or triphenylphosphine,
to 1 mole of the azide compound compound, the reducing agent is used in 1 mole or more, preferably, 1 to 2 mole.
[0152] The reaction temperature in the Mitsunobu reaction is usually from -70 to 1 00°C, preferably, within the range
from 20 to 50 °C.The reaction time is usually from 5 minutes to 48 hours, preferably, from 30 minutes to 24 hours.
[0153] The reaction temperature in the cleavage reaction of phthalimide group using hydrazine, is usually from 0 °C
to the boiling point of the solvent, preferably, from 20 to 100°C. The reaction time is usually from 5 minutes to 48 hours,
preferably, from 30 minutes to 24 hours.

(il-e)

46

EP 1 199 306 A1

[0154] The reaction temperature in the reduction reaction of transforming azide compound compound to amine com-
pound using hydrogenated metal complex, is usually -70 to 1 50°C, preferably, within the range from 20 to 50 °C. The
reaction time is usually from 5 minutes to 48 hours, preferably, from 10 minutes to 10 hours. In case of using triphe-
nylphosphine as a reductive agent, the temperature is usually from 20 °C to the boiling point of the solvent, preferably,
5 within the range from 30 to 1 00°C. The reaction time is usually from 1 0 minutes to 48 hours, preferably, from 30 minutes
to 24 hours. The reaction temperature in the hydrogenation reduction, is usually from 0 to 100 °C, preferably, within
the range from 20 to 50 °C. The reaction time is usually from 1 0 minutes to 48 hours, preferably, from 1 0 minutes to
24 hours.

[0155] After the completion of the reaction, followed by routine treatment, the compound of formula (ll-e) can be
10 obtained, if necessary, by protecting the protective group of hydroxyl group, amino group and carboxyl group.
[0156] In the compound of formula (ll-d), the compound of formula (ll-d.,) ;

[in the formula, Ar d1 represents Ar 0 given above, which comprises the substituent of -T 1 -CH(R d1 )-OH(wherein, R d1
represents hydrogen, or lower alkyl group, arylalkyl group, aromatic ring group beteroaromatic ring group, each of
25 which may have a protected substituents, or a saturated or unsaturated aliphatic cyclic group which may contain one
or more hetero atom selected from the group consisting of nitrogen, oxygen and sulfur, T 1 has the meaning given
above), X, Y, Z, R 10 , R 20 , R3o> ^40* ^50 anc ' * ne formula — have the meaning given above] is subject to oxidation to
afford the compound of formula (ll-d 2 );

30

v n>>_ hn H (ii-d 2 )

R 40 R 50

[in the formula, Ar d2 represents Ar 0 given above, which comprises the substituent of -T 1 -C(=0)-R d1 (wherein, R d1 and
40 T 1 have the meanings given above), X, Y, Z, R 10 , R 2 q, ^30* ^40> FUn ar| d the formula — have the meaning given above],
followed by the reductive amination to give the compound of formula (ll-d 3 );

[in the formula, Ar d3 represents Ar 0 given above, which comprises the substituent of -T-,-CH(R d1 )-NR d2 R d3 (wherein,
R d2 and R d3 represent, the same or different, hydrogen, or lower alkyl group, arylalkyl group, aromatic ring group,
55 hetero aromatic ring group, which may have an substituent optionally protected, or saturated or unsaturated aliphatic
cyclic group which may have one or more hetero atom selected from a group consisting of nitrogen, oxygen and sulfur,
T 1 has the meaning given above), X, Y, Z, R 10 , R 20 , R 30 , R 40 , R 50 and the formula — have the meaning given above].
[0157] As the reaction wherein the compound of formula (ll-d 2 ) can be prepared by oxidizing the compound of formula

47

EP 1 199 306 A1

(ll-d-i), the well-known oxidization reaction can be used.

[0158] In the reductive amination reaction between the compound of formula (ll-d 2 ) and Rd2^d3^H (in the formula,
R d2 and R d3 have the meanings given above), to 1 mole of the compound of formula (ll-d 2 ), R c i2' = 'd3NH is used in 1
mole or more, preferably 3 to 5 mole, and a reducing agent such as sodium borohydride ortriacetoxy sodium borohy-
dride is used in 1 mole or more, preferably 3 to 5 mole. In the reaction, if necessary, molecular sieve 3A is used in 3
times of the compound of formula (ll-d 2 ) by weight.

[0159] The reaction is carried out usually in an inactive solvent such as chloroform and methanol or mixed solvent
thereof. The reaction temperature is usually from 20 °C to the boiling point of the solvent, preferably from 20 to 60 °C.
[0160] The process wherein the compound of formula (ll-d 3 ) can be prepared by starting from the compound of
formula (ll-d-|) via the compound of formula (ll-d 3 ) can be carried out after the moiety of urea is protected according to
the transformation method B.

[01 61 ] The compound of formula (I) can be prepared by optionally eliminating the protective group of the compounds
of formula (ll-c), formula (ll-d) and formula (ll-e) obtained according to the above method. The method of cleavaging
the protective group varies depending on the type of the protective group and the stability of the desired compound
and usually may follow the general method described in the literature given above, or a similar method thereof.

Transformation Method B

[0162] This method is a method of the transformation reaction after the urea moiety is protected.
The compound of formula (XI);

[in the formula, Ar co , X, Y, Z, R-| 0 , R 20 , R3o> R50 anc ' tne formula have the meanings given above] can be
produced by stirring the compound of formula (ll-c);

[in the formula, Ar co represents Ar 0 given above, which comprises the substituent of -T^ORg (wherein, R 6 and T-) have
the meanings given above), X, Y, Z, R 10 , R 20 , R30: R4C R50 anc ' the formula ™ have the meaning given above] in imine
prepared from tert-butylamine and paraformaldehyde. The compound of formula (XI) can be a starting compound of
the present transformation method, and the compound of formula (XII);

48

EP 1 199 306 A1

R50

O

[in the formula, Ar d0 represents Ar 0 given above, which comprises the substituent of -T-| -OH (wherein, T 1 has the mean-
ing given above), X, Y, Z, R 10 , R 2 q, FUo> R50 and the formula ™ have the meanings given above] can be prepared
by eliminating the protective group of hydroxyl group of the compound of formula (XI).

[0163] In the reaction for preparing the compound of formula (XI), to 1 mole of the compound of formula (ll-c), imine
prepared from tert-butylamine and paraformaldehyde is used in 3 to 5 mole, preferably 4 mole.

[0164] The above reaction can be usually carried out in an inactive solvent such as chloroform, dichloromethane
and tetrahydrofuran, and so on.

[0165] The reaction temperature is usually from 50 °C to the boiling point of the solvent, from 80 to 150 °C. The
reaction time is usually from 12 to 72 hours, preferably from 24 to 72 hours. If necessary, one drop of acid such as
sulfuric acid may be added to accelerate the reaction.

[0166] The compound of formula (XII) can be derived from the compound of formula (XI), by the transformation
method for preparing the compound of formula (ll-d) from the compound of formula (ll-c).

[0167] The compound of formula (XII), which is the key intermediate for preparing the compound of formula (I), can
be derived from the compound of formula (XII) or its derivative according to, for example, the transformation method
C to E described hereinafter.

Transformation method C

[0168] By reacting the compound of formula (XII);

[in the formula, Ar d0 , Y, Z, R 10 , R 2 o, R30, FUo> R50 anc ' tne formula ™ have the meanings given above], with the com-
pound of formula (XIII);

[in the formula, Ar 2 represents phenyl substituted with 1 or 2 nitro group, R 8 represents benzyl substituted with 1 to 3
methoxy groups] to give the compound of formula (XIV);

Ar 2 -

NHR 8

(XIII)

49

EP 1 199 306 A1

[in the formula, Ar d1 represents Ar 0 given above, which comprises the substituent of -T 1 -N(R 8 )S0 2 Ar 2 (wherein, T 1; R 8
and Ar 2 have the meanings given above), X, Y, Z, R 10 . R 20 , R50 and the formula — have the meanings given

[0169] The reaction is carried out by Mitsunobu reaction. To 1 mol of the compound of formula (XII), the compound
of formula (XIII) is used 1 mole or excess mole, preferably 1 to 3 mole. For example, the compound of formula (XII) is
activated by reacting with azodicarboxylic acid diester such as diethylazadicarboxylate and phosphines such as triphe-
nylphosphine, which is further reacted with the compound of formula (XIII) to obtain the compound of formula (XIV).
[0170] The reaction is usually carried out in an inactive solvent such as haloalkenes like dichloromethane and chlo-
roform, ethers such as ethyl ether and tetrahydrofuran or a mixed solvent thereof and so on.

[0171] To 1 mole of the compound of formula (XII), azodicarboxylic acid diester such as diethylazadicarboxylate and
phosphines such as triphenylphosphine are used 1 mole or more, preferably 1 to 3 mole.

[0172] The reaction temperature is usually from 0 °C to the boiling point of the solvent, preferably from 20 to 40 °C.
[0173] The reaction time is usually from 1 hour to 24 hours, preferably from 2 to 24 hours.

[0174] After the completion of the reaction followed by the ordinary treatment, the crude compound of formula (XIV)
can be obtained, which is purified according to the conventional method to obtain the compound of formula (XIV).
[0175] The compound of formula (XV);

[in the formula, Ar d2 represents Ar 0 given above, which comprises the substituent of -T 1 -NHS0 2 Ar 2 (wherein, T 1 and
Ar 2 have the meanings given above), X, Y, Z, R 10 , R 20 , R 30 , R 40 , R 50 and the formula ™ have the meanings given
above], is prepared by the ordinary cleavage of aralkyl group as amino-protecting group described in the literature
given above.

[0176] In the reaction for preparing the compound of formula (XVI);

above].

R 40 R 50

[in the formula, Ar d3 represents Ar 0 given above, which comprises the substituent of -T 1 -N(R q )S0 2 Ar 2 (wherein, R (

50

EP 1 199 306 A1

T-i and Ar 2 have the meanings given above), X, Y, Z, Ri 0 , R 20 , ^30* FUo> R50 an< ^ the formula ™ have the meanings
given above], from the compound of formula (XV), to 1 mole of the compound of formula (XV), R q -OH (wherein Rq has
the meaning given above) is used in 1 or excess mole, preferably 1 to 3 mole. Said reaction can be carried out according
to the similar reaction of the compound of formula (XII) with the compound of formula (XIII). Thus, the reaction condition
5 and so on can apply to said reaction.

[0177] The reaction for preparing the compound of formula (XVII);

[in the formula, Ar d4 represents Ar 0 given above, which comprises the substituent of -T^NHRqfwherein, R q and T 1
20 have the meanings given above). X, Y, Z, R-|q, R 20 , R3o> FUo* ^50 anc ' tne formula ™ have the meanings given above],
from the compound of formula (XVI), can be carried out according to ordinary hydrolysis of arylsulfonamide, in which
for example, thiophenol, sodium carbonate are used in an inactive solvent. Said solvent is, for example, preferably
dimethylformamide, and so on.

[0178] According to the reaction condition similar to that of the reaction of transforming the compound of formula
25 (XVI) into the compound of formula (XVII), the compound, in which R q has a convertible substituent, can be prepared
by introduction of an appropriate substituent on the compound of formula (XVI).

[0179] The reaction temperature is usually from 20 °C to the boiling point of the solvent, preferably from 20 to 80°C.
[0180] The reaction time is usually 2 to 48 hours, preferably, 2 to 24 hours.
[0181] The reaction for preparing the compound of formula (ll-f);

30

35

40 [in the formula, Ar d4 represents Ar 0 given above, which comprises the substituent of -T1 -NHR q (wherein, R q and T 1
have the meanings given above), X, Y, Z, R 10 , R 20 , R40. R50 ar| d the formula ™ have the meanings given above],
from the compound of formula (XVII), can be carried out by reacting the compound of formula (XVII) with an appropriate
acid such as hydrochloric acid, trifluoroacetic acid and so on. If necessary, the reaction can be carried out in a mixture
of said reagent(s) and an inactive solvent such as tetrahydrofuran and chloroform.

45 [0182] The similar reaction for the compound, in which an appropriate substituent is introduced can be carried out
by applying the transformation reaction of the substituent on R q of the compound of formula (XVI).
[0183] The compound of formula (ll-f) can be prepared by reductive amination of the compound of formula (XXIII).
In said method, the compound of formula (ll-f) can be prepared by deprotecting the protective group for urea moiety
using for example, hydrochloric acid or trifluroacetic acid, before or after the reductive amination reaction.

50 The protective group of the intermediate in each step of the preparation method can be removed appropriately at each
step and at the final step to obtain the compound of formula (I).

[0184] The method of eliminating the protective group depends on the type of the protective group and the stability
of the desired compound and usually may follow the method described in the literature given above or a similar method
thereof.

55

Transformation method D

[0185] In the present transformation method, by using the compound of formula (XVII) prepared in the transformation

51

EP 1 199 306 A1

method C, the compound of formula (XIX);

[in the formula, Ar d5 represents Ar 0 given above, which comprises the substituent of -T-,-NR q -T 2 -R p (wherein, T 2 rep-
resents carbonyl group or sulfonyl group, R p , R q , T 1; Ar 2 have the meaning given above), X, Y, Z, R 10 , R 20 , R30, FUo*
R 50 and the formula ™ have the meanings given above] is obtained, and then the compound of formula (ll-g);

[in the formula, Ar d5 represents Ar 0 given above, which comprises the substituent of -T.|-l\IR q -T 2 -R p (wherein ; T 1( Ar 2
Rp, R q and T 2 have the meanings given above), X, Y, Z, R-| 0 , R 20 , R 30 , R 40 , R 50 and the formula ~ have the meanings
given abovejcan be prepared.

[0186] The reaction for preparing the compound of formula (XIX) from the compound of formula (XVII) is carried out
by reacting the compound of formula (XVII) with the carboxylic acid, sulfonic acid or the reactive derivative thereof
represented by compound of formula (XVIII)R p -T 2 -OH[in the formula, R p and T 2 have the meanings given above]. The
examples of reactive derivatives of carboxylic acid or sulfonic acid of formula (XVIII) include, for example, acid halide,
mixed anhydride, active ester, active amide, and so on.

[0187] In case where carboxylic acid of formula (XVIII) is used, the reaction is carried out preferably in the presence
of a condensing agent such as N ,N'-dicyclohexylcarbodiimide, 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide, 2-chlo-
ro-1 ,3-dimethylimidazolylchloride, and so on.

[0188] In the reaction of the compound of formula (XVII) with the compound of formula (XVIII), to 1 mole of the
compound of formula (XVII), the compound of formula (XVIII) is used in 1 mole or more, preferably 1 to 5 mole.
[0189] The reaction is usually carried out in an inactive solvent. Said solvent includes haloalkane such as dichlo-
romethane, chloroform and so on, ethers such as ethyl ether, tetrahydrofuran, and so on, aromatic hydrocarbons such
as benzene, toluene, and so on, non-proton polar solvents such as dimethylformamide, acetone, ethyl acetate, or a
mixed solvent thereof.

[0190] The reaction temperature is usually from -20 °C to the boiling point of the solvent, preferably from 0 to 50 °C.
[0191] The reaction time is usually from 1 0 minutes to 48 hours, preferably from 30 minutes to 24 hours.
[0192] The reaction can also be carried out in the presence of a base. Said base includes an inorganic base such
as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium bicarbonate, potassium carbonate, sodium
hydrogen carbonate, or an organic base such as triethylamine, N-ethyldiisopropylamine, pyridine, 4-dimethylaminopy-
ridine, N,N-dimethylaniline.

[0193] To 1 mole of the compound of the formula (XVIII), the base is used in 1 mole or more, preferably 1 to 5 mole.
[0194] The acid halide of formula (XVIII) can be prepared by reacting carboxylic acid or sulfonic acid of formula
(XVIII) with halogenating agent, following a conventional method. The halogenating agent includes thionylchloride,
phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, oxyzly chloride,
phosgene, and so on.

[0195] The mixed anhydride of carboxylic acid of formula (XVIII) can be prepared by reacting carboxylic acid of
formula (XVIII) with chloroformic ester such as ethyl chloroformate or aliphatic carboxylic acid chloride such as acetyl
chloride.

[0196] The active ester of carboxylic acid of formula (XVIII) can be prepared by reacting carboxylic acid of formula
(XVIII) with, for example, N-hydroxyl compound such as N-hydroxysucuimide. N-hydroxyphthalimide, 1 -hydroxyben-

52

EP 1 199 306 A1

zotriazole, phenol compound such as 4-nitrophenol, pentanchlorophenol, according to the conventional method in the
presence of a condensing agent such as N,N'-dicyclohexylcarbodiimide, 1 -ethyl-3-(3-dimethylaminopropyl)carbodiim-
ide, and the like.

[0197] The active amide of carboxylic acid of formula (XVIII) can be prepared by reacting carboxylic acid of formula
(XVIII) with, for example, 1 ,1 '-carbonyldiimidazole, 1 ,1'-carbonylbis(2-methylimidazole), according to the conventional
method.

[01 98] The compound of formula (I) can be prepared, if appropriate, by deprotecting the protective group of compound
of formula (XIX) prepared above, to afford the compound of formula (ll-g), followed by further elimination of the pro-
tective group.

[0199] The compound of formula (ll-g) can be prepared by reacting the compound of formula (XIX) with an appropriate
acid such as hydrochloric acid and trifluoroacetic acid, optionally in mixture with the inactive solvent such as tetrahy-
drofuran and chloroform.

[0200] Also, the compound of formula (ll-g) can be prepared according to this preparation method using the com-
pound of formula (ll-f) in the transformation method A.

Transformation method E

[0201] In this method, using the compound of formula (XII), the compound of formula (XX);

[in the formula, Ar h0 represents Ar 0 given above, which comprises the substituent of -T.|-OR p (wherein ; R p and T 1 have
the meanings given above), X, Y, Z, R 10 , R 20 , R30, R50 anc l tne formula --- have the meanings given above], can
be obtained and then the compound of formula (ll-h);

[in the formula, Ar h0 represents Ar 0 given above, which comprises the substituent of -T-|-0-R p (wherein, R p andT-| have
the meanings given above), X, Y, Z, R 10 , R2o> ^30* ^40* ^50 anc ' tne formula ™ have the meanings given above] can
be prepared.

[0202] The reaction for preparing the compound of formula (XX) from the compound of formula (XII) is carried out
by following various synthetic methods and reaction contidions for transforming alcohol into ether. For example, aryl
ether can be prepared by reacting aryl alcohol with diethylazodicarboxylate and triphenylphosphine(what is called,
Mitsunobu reaction). Alkyl ether can be prepared by reacting halogen compound (some of the compounds are com-
mercially available), or sulfonate ester such as methanesulfonate ester, each of which can be prepared from alcohol
represented by formula (XX I )Rp-OH (wherein, R p has the meaning given above) in the presence of a base.
[0203] Furthermore, the method for synthesizing alkyl ether and aryl ether is illustrated by for example, transforming
the compound of formula (XII) into the corresponding halogen compound or sulfonate ester followed by reacting with
an alcohol represented by formula (XXI) R p -OH in the presence of a base. The transformation of said alcohol into said
halogen compound is usually carried out by an ordinary method, for example, reacting with carbon tetra-bromide and
triphenylphosphine in an inactive solvent such as carbon tetrachloride and the like. Similarly, sulfonate ester such as
methanesulfonate ester can be prepared by reacting with methanesulfonyl chloride and a base such as triethylamine

53

EP 1 199 306 A1

in an inactive solvent such as ethyl acetate.

[0204] The compound of formula (I l-h) can be prepared appropriately in combination with cleavage of the protective
group for hydroxyl group, amino group and carboxyl group of the compound of formula (XX) obtained above.
[0205] The above reaction is usually carried out in an inactive solvent. As said solvent, tetrahydrofuran, chloroform,
5 dimethoxy ethane, benzene, toluene, and the like are preferably used in Mitsunobu reaction; haloalkanes such as car-
bon tetrachloride, chloroform, and the like are preferably used in the halogenation; dichloromethane, chloroform, tet-
rahydrofuran, benzene, ethyl acetate, dimethylformamide are preferably used in sulfonation.

[0206] In Mitsunobu reaction, to 1 mole of the compound of formula (Xll).the amount of diethylazadicarboxylate,
phosphine and aryl alcohol are each 1 mole or more, preferably 1 to 5 mole.

10 [0207] In the reaction of the compound of formula (XII) after halogenating the alcohol of formula (XII), to 1 mole of
the alcohol of formula (XXI), the halogenating agent is used in 1 mole or more, preferably 1 to 3 mole. In the next
reaction of the compound of formula (XII), to 1 mole of the compound of formula (XII), the halogenating agent is used
in 1 mole or more, preferably 1 to 5 mole. To 1 mole of the halogenating agent, the base is used in 1 mole or more,
preferably 1 to 5 mole. In the reaction of compound of formula (XII) after transforming the alcohol of formula (XXI) to

*s sulfonate ester, to 1 mole of the alcohol of formula (XXI), the sulfonating agent is used in 1 mole or more, preferably
1 to 3 mole. To 1 mole of the sulfonating agent, the base is used in 1 mole or more, preferably 1 to 5 mole. In the next
reaction of the compound of formula (XII), to 1 mole of the compound of formula (XII), the sulfonate ester is used in 1
mole or more, preferably 1 to 5 mole. To 1 mole of the sulfonate ester, the base is used in 1 mole or more, preferably
1 to 5 mole.

20 [0208] In case where the compound of formula (XII) is first converted to the corresponding halide or sulfonate ester,
which is then reacted with the alcohol of formula (XXI) in the presence of base, the reaction can be carried out according
to the procedure described above.

[0209] In the Mitsunobu reaction described above, the reaction temperature is usually from -70 to 1 00 °C, preferably
from 20 to 50 °C. The reaction time is usually from 5 minutes to 48 hours, preferably from 30 minutes to 2 to 24 hours.

25 in the reaction of the compound of formula (XII) after the halogenation of the alcohol of formula (XXI), the reaction
temperature is usually from 0 °C to the boiling point of the solvent, preferably from 20 to 1 00°C. The reaction time is
usually from 5 minutes to 48 hours, preferably from 30 minutes to 24 hours. In the reaction of the compound of formula
(XI I) after the transformation of the alcohol of formula (XXI) to the sulfonate ester, the reaction temperature is usually
from 0 to 1 00 °C, preferably from 0 to 30 °C. The reaction time is usually from 5 minutes to 48 hours, preferably from

30 10 minutes to 1 0 hours. In case where the compound of formula (XII) is first converted to the corresponding halide or
sulfonate ester, which is then reacted with the alcohol of formula (XXI) in the presence of base, the reaction can be
carried out according to the procedure describe above.

[0210] After the completion of the reaction followed by the ordinary treatment, the compound of formula (ll-h) is
obtained optionally in combination with the deprotecting reaction of the protective group for hydroxyl group, amino
35 group and carboxyl group, and then the compound of formula (I) is obtained by deprotecting of all protective groups.
[0211] The deprotecting method of a protective group depends on the type of the protective group and the stability
of the desired compound, which can be carried out for example, if appropriate, according to the literature method
described above or a similar method thereof.

40 Transformation method F

[0212] In this method, using the compound of formula (XII), the compound of formula (XXII);

[in the formula, Ar j0 represents Ar 0 given above, which comprises the substituent of -T^CHO (wherein, T-| has the
meaning given above), X, Y, Z, R 10 , R 2 o> R3o> R4o> R50 ar| d tne formula ™ have the meanings given above], can be
obtained and then the compound of formula (XXIII);

45

50

R 40 R50

54

EP 1 199 306 A1

P^o ^20 y"^

V^JGL (xxiid

R40 R50

10

[in the formula, Ar i2 represents Ar 0 given above, which comprises the substituent of -T-,-CH=R v (wherein, T 1 has the
meaning given above, R v represents an ester group), X, Y, Z, R 10 , R 20 , R3o> ^40* ^50 anc ' tne formula ™ have the
meanings given above] can be prepared.

[0213] In the reaction, to 1 mole of the compound of formula (XII), manganese dioxide is used in 1 mole or more,
*s preferably 20 mole. After the compound of formula (XXII) is obtained, the compound of formula (XXIII) can be prepared
by reacting with dialkylphosphonoacetate and an appropriate base such as sodium hydride in 1 mole or more, prefer-
ably, 3 to 5 mole, respectively. The reaction is carried out usually in an inactive solvent. Said solvent includes tetrahy-
drofuran and ethyl ether and the like.

[0214] The reaction temperature in synthesizing the compound of formula (XXII) from the compound of formula (XII)
20 is usually from 0°C to the boiling point of the solvent used, preferably from 20 to 50 °C. The reaction temperature in
synthesizing the compound of formula (XXIII) from the compound of formula (XXII) is usually from -78 to 20 °C, pref-
erably from -78 to 0 °C.

[0215] By either Diels-Alder reaction or well known 1 ,3 dipolar addition reaction between the compound of formula
(XXIII) and reactive diene compound followed by the treatment with acid, the compound of formula (ll-i);

25

^V^-HN N (ll-O

°

rt 40 R 50

35 [in theformula, Ar j2 represents Ar 0 given above, which comprises the substituent of -T^Cy (wherein, T 1 has the meaning
given above, Cy represents aliphatic cyclic group which may contain hetero atom and which may be substituted), X,
Y, Z, R 10 , R2O' ^30' ^40* R50 anc ' tne formula ™ have the meanings given above] can be prepared.
[0216] To 1 mole of the compound of formula (XXIII), the reactive diene is usually used in 1 mole or more, preferably
1 0 mole.

40 [0217] The above reaction is usually carried out in an inactive solvent. Said solvent includes preferably, haloalkanes
such as dichloromethane and chloroform, or acetonitrile and so on.

[0218] The reaction temperature is usually from 0 °C to the boiling point of the solvent used, preferably, within the
range from 20 to 120 °C.

[0219] The compound of formula (ll-i) can be prepared from the compound obtained above by following the method
45 similar to the process for preparing the compound of formula (ll-f) from the compound of formula (XVII).

Transformation method G

[0220] By reacting the compound of formula (XXIV);

50

55

J* 2 Q
"40 R 50

55

EP 1 199 306 A1

[in the formula, Aip represents Ar 0 given above, which comprises the substituent of -Sn-R w 3(wherein, R w represents
lower alkyl group), X, Y, Z, R 10 , R 2 q, ^30* ^40* ^50 anc ' * ne formula — have the meanings given above] with the com-
pound of formula (XXV);

R x -L 1 (XXV)

[in the formula, R x represents cyclic or non-cyclic aliphatic group, aromatic group, or hetero-aromatic group, each of
which may have protected substituent(s) and in which carbon atom which l_i binds to may have an unsaturated bond
to which Ar^ binds, L 1 represents halogen atom or trifluoromethanesulfonyloxy group], the compound of formula (ll-j);

VSr-"sA . ("-J)

^40 R 50

[in the formula, Ar^ represents Ar 0 given above, which comprises the substituent of -R x (wherein, R x represents cyclic
or non-cyclic aliphatic group, aromatic group, or hetero-aromatic ring group, each of which may have protected sub-
stitutent(s) and in which carbon atom to which Ar^ binds may have an unsaturated bond), X, Y, Z, R 10 , R 2 o, R3o> FUo*
R 50 and the formula ™ have the meanings given above] can be prepared.

[0221] In the reaction, to 1 mole of the compound of formula (XXIV), the compound of formula (XXV) is used in 1
mole or more, preferably 1 to 3 mole. Preferably, the reaction can be carried out by adding for example, palladium
catalyst such as tris(dibenzelidenacetone) dipalladium(0)(Pd 2 (dba)3), phosphine ligand such as triphenylphosphine
and if necessary adding lithium chloride, in the presence of inactive gas.

[0222] The reaction is usually carried out in an inactive solvent. Said inactive solvent includes preferably, ethers such
as dioxane and tetrahydrofuran, aromatic hydrocarbons such as toluene.

[0223] The reaction temperature is usually for 20 °C to the boiling point of the inactive solvent used, preferably from
50 to 130°C.

Transformation method H

[0224] From the compound of formula (Xll-i);

[in the formula, Ar k0 represents Ar 0 given above, which comprises the substituent of -(CH 2 ) 2 -OH, Y, Z, R 10 , R 20 , R
R 40 , R 50 and the formula -~ have the meanings given above], the compound of formula (XXVI);

56

EP 1 1 99 306 A1

(XXVI)

[in the formula, Ar k1 represents Ar 0 given above, which comprises the substituent of -CH=CH 2 , X, Y, Z, R 10 , R 20 , R 30 ,
R 40 , R 50 and the formula ™ have the meanings given above] can be synthesized, and then reacting said compound
with the compound of formula (XXVII);

Ry-SH (XXVII)

[in the formula, R y has the aliphatic group or aromatic group, each of which may have protected substituent(s)] to
prepare the compound of formula (ll-k);

HNJ N

o

H (ll-k)

[in the formula, Ar k2 represents Ar 0 given above, which comprises the substituent of -(CH 2 ) 2 -SR y (wherein, R y has the
meanings given above, X, Y, Z, R 10 , R 20 , FUo* R50 anc ' the formula ~ have the meanings given above)].
[0225] In the reaction for preparing the compound of formula (XXVI) from the compound of formula (Xll-i), to 1 mole
of the compound of formula (Xll-i), for example, methanesulfonyl chloride is used in 1 mole or more, preferably 1 to 3
mole; an appropriate base, for example, aliphatic tertiary amine such as 1 ,8-diazabicyclo[5,4,0]undecan-7-ene(DBU)
is used in 1 or more mole, preferably 1 to 3 mole.

[0226] The reaction is carried out usually in an inactive solvent. Said solvent includes preferably, tetrahydrofuran
and ethyl acetate. The reaction temperature is usually from 20 °C to the boiling point of the inactive solvent used,
preferably from 20 to 50 °C.

[0227] In the reaction for preparing the compound of formula (ll-k) from the compound of formula (XXVI), to 1 mole
of the compound of formula (XXVI), for example, R y -SH is used in 1 mole or more, preferably 1 to 5 mole; and the
base such as sodium ethoxide is used in 1 mole or more, preferably 1 to 5 mole. The compound of formula (ll-k) is
therefore obtained by the completion of the above reaction followed by the treatment with acids such as hydrochloric
acid.

[0228] The reaction is usually carried out in alcohols such as methanol and ethanol. The reaction temperature is
usually from 0 °C to the boiling point of the solvent used, preferably from 0 to 50°C.

[0229] Applying the method similar to the method for preparing the compound (ll-i) from the compound of (XXIII) to
the compound of (XXVI), the compound of formula (ll-i 1 );

(ii-i')

57

EP 1 199 306 A1

[in the formula, Ar i3 represents Ar 0 given above, which comprises the substituent of -T-i-Cy 1 (wherein, l~i has the mean-
ing given above, Cy 1 has an aliphatic cyclic group, which may have protected substituents and which may contain
heteroatom), X, Y, Z. R 10 , R 2 q, R40, R50 and the formula ™ have the meanings given above] can be prepared.
[0230] The above reaction is carried out under the condition similar to the reaction condition for preparing the com-
pound (ll-i) from the compound of (XXIII).

[0231] Next, the method for preparing starting materials of the present invention is illustrated as follows.
[0232] As described above, the compound of formula (I) can be prepared by using the compound of formula (III),
the compound of formula (IV), the compound of formula (V) and the compound of formula (VI) as starting materials.
The starting materials can be prepared from the known compounds by per se known general synthetic method. The
main synthetic routes are illustrated as follows.

[0233] The compound of formula (III) can be prepared by using the synthetic methods Ato J; the compound of formula
(IV) can be prepared by using the synthetic methods K to M; and the compound of formula (V) can be prepared by
using the synthetic method N.

[0234] Among the compound (III) used in the preparation method A, the compound wherein X is nitrogen, and Y is
c=0, that is,

the compound of formula (lll-i);

Tl NH 2 ("l-O

R 40 R50

[in the formula, X-| is nitrogen, Y-| is CO, Z, R 10 , R 20 , R<4o> ^50 anc ' tne formula ™ have the meanings given above]
can be prepared by using the synthetic method A.

Synthetic method A

[0235] This method comprises converting the carboxylic acid of formula (1);

OH Q

[in the formula, Q is halogen atom, R 40 and R 50 have the meanings given above] to its reactive derivative (1 '), reacting
the active derivative (1 1 ) with the compound of formula (2);

f"t R 30 (2)

H H

[in the formula, X, R 10 , R 20 , R30 anc ' Z have the meanings given above] to afford the compound of formula (3);

58

EP 1 199 306 A1

[in the formula, X, R 10 . R 20 , F^o* ^40' ^50* Q anc ' ^ have the meanings given above], then subjecting the compound
of formula (3) to an intramolecular ring closure reaction using palladium as a catalyst to afford the compound of formula
(4) [in the formula, X, R 10 , R 20 , R30 ar| d Z have the meanings given above] to obtain the compound of formula (4);

25 [in the formula, X, R 10! R20' ^30* ^40> ^50 anc ' ^ have the meanings given above], and then reacting with a reducing
agent.

[0236] The reaction between the active derivative (1 ') of carboxylic acid of formula (1 ) and the compound of formula
(2) can be carried out by method similar to the process wherein the compound (XIX) is produced from the compound
of formula (XVII) in the above-mentioned transformation method, thus the similar reaction condition can be applied.
30 [0237] In the reaction of preparing the compound of formula (4) from the compound of formula (3), to 1 mole of the
compound of formula (3), palladium complex such as tetrakistriphenylphosphine palladium is used in 5 to 50% by
weight, preferably, 10 to 20% by weight; and the base such as potassium acetate is used in 2 to 10 mole, preferably
2 to 5 mole.

[0238] The reaction is carried out usually in an inactive solvent. Said solvent includes halogenated hydrocarbons
35 such as dichloromethane, chloroform, and the like; ethers such as ethyl ether, tetrahydrofuran, dioxane, and the like;
aromatic hydrocarbons such as benzene, toluene, and the like; aprotic polar solvent such as dimethylformamide, ac-
etone, ethyl acetate, and the like; or a mixed solvent thereof.

[0239] The reaction temperature is usually 20 °C to the boiling point of the solvent used, preferably, within the range
from 50 to 1 00 °C. The reaction time is usually 30 minutes to 24 hours, preferably 5 to 24 hours.
40 [0240] Among the compound of formula (lll-i), the compound (Ml-i a ), in which the five- or six- membered ring formed
by R 20 with R 10 and X is unsaturated, and the compound (lll-i b ), in which the five- or six- membered ring formed by
R 20 with R 10 and X is saturated can be prepared from the compound of formula (4) under an appropriate condition
selected.

[0241] The compound (lll-i a ) which is unsaturated can be obtained in the reaction where, to 1 mole of the compound
45 of formula (4), for example, iron dust used in is 5 to 20 mole, preferably 5 to 1 0 mole in the presence of hydrochloric
acid. The compound (lll-i b ) which is saturated can be prepared by subjecting the compound of formula (4) to hydro-
genation. In the reaction, to 1 mole of the compound(4), for example, 10% palladium carbon catalyst is used 5 to 50
% by weight, preferably, 1 0% to 20% by weight.

[0242] The reaction is carried out usually in an inactive solvent. Said solvent includes alcohol such as methanol and
50 ethanol for the reaction using iron dust in the presence of hydrochloric acid, ethers such as ethyl ether and tetrahydro-
furan, alcohols such as methanol and ethanol or a mixed solvent thereof for the hydrogenation.

[0243] In the reduction reaction using iron dust in the presence of hydrochloric acid, the reaction temperature is
usually 0°C to the boiling point of the solvent used, preferably, within the range from 20 to 50 °C; and the reaction time
is 30 minutes to 24 hours, preferably 30 minutes to 2 hours. In the hydrogenation, the reaction temperature is usually
55 0 °C to the boiling point of the solvent used, preferably, within the range from 20 to 50 °C; and the reaction time is 1
hour to 48 hours, preferably 5 to 24 hours.

[0244] After the completion of the reaction followed by routine treatment method optionally in combination with de-
protection of the protective group of hydroxyl group, amino group and carboxyl group can be prepared the compound

59

EP 1 199 306 A1

of formula (III).

[0245] The cleprotecting method of the protective group varies depending on the type of the protective group and
the stability of the desired compound, and may follows the appropriate method described above or a similar method
thereof.

5 [0246] The compound (wherein, X is nitrogen, Y is CO, Z is carbon atom) of the formula (Ill-ii);

(iii-H)

15

[in the formula, R 2i represents hydrogen atom or a hydroxyl group, R 31 represents hydrogen atom, R 10 , R 40 , R 50 and
X 1 have the meanings given above], which is a starting material in the preparation method A, can be prepared as follows.

Preparation method B

20

[0247] The compound of (Ill-ii) can be prepared by subjecting the compound of formula (5);

no 2 (5)

[in the formula, R 40 and R 50 have the meanings given above] to alkylation by Mitsunobu reaction followed by the
reduction with sodium borohydride to obtain the compound of formula (6);

[in the formula, X 1 ,Ri 0 , R4.0 ar| d R50 have the meanings given above], followed by hydrogenation using palladium
catalyst.

45 [0248] The Mitsunobu reaction of the compound of formula (5) can be carried out by a method similar to method for
preparing the compound of formula (XX) from the compound of formula (XII). The compound of formula (6) can be
prepared by applying the well-known reduction reaction using sodium borohydride after Mitsunobu reaction.
[0249] The compound of formula (Ill-ii) can be prepared from the compound of formula (6) by applying hydrogenation
reaction using for example, palladium catalyst such as palladium hydroxide. Said reaction is carried out usually in an

50 inactive solvent. The solvent includes tetrahydrofuran and methanol. The reaction temperature is usually 20 °C to the
boiling point of the solvent used, preferably, within the range from 20 to 50 °C.

[0250] By controlling the reaction condition of the hydrogenation appropriately, the compound of formula (W-ii a )
(wherein, R 2 i is hydrogen atom, R 10 , R 31 R 40 and R 50 have the meanings given above) and the compound of
formula (Ml-ii b ) (wherein, R 21 is hydroxyl group, X 1 ,R-| 0 , R31, R 40 and R 50 have the meanings given above) can be
55 prepared.

[0251] The compound of formula (lll-iii);

60

EP 1 199 306 A1

[in the formula, T 3 is single bond, or alkyl group or aralkyl group which may have protected substituent(s) having 1 to
3 carbon atoms, R 10a and R 2 o a are > tne same or different, and independently optionally substituted saturated or un-
saturated hydrocarbon group, R 80 is a hydrogen atom or a saturated or an unsaturated hydrocarbon group, which may
form a ring structure by binding to either R 2 o a °rT 3 . and which may have optionally protected substituent(s), R 40 and
R 50 have the meanings given above], which is a starting material of the preparation method A, can be prepared as
follows.

Synthetic method C

[0252] The compound of formula (lll-iii) can be prepared by undertaking the Mitsunobu's reaction of the compound
of formula (5) with the compound of formula (7);

R 10a -CH(OH)-T 3 -CO-R 20a (7)

[in the formula, T 3 , R-|0a> and ^20a have the meanings given above] followed by reduction using sodium borohydride
and then ring closure under an acidic condition to produce the compound of formula (8);

no 2 (8)

[in the formula, T 3 . R-ioa, R 20a, R 40 and R so have the meanings given above], which is subjected to hydrogenation to
obtain the compound of formula (lll-iii 1 );

(lll-iii 1 )

[in the formula, T 3 , Ri 0a , ^203, R40 an d R50 have the meanings given above] followed by introducing a substituent using
R 80 -I_jij(wherein, L iM is halogen atom).

[0253] The Mitsunobu reaction of the compound of formula (5) can be carried out by a method similar to the method
for preparing the compound of formula (XX) from the compound of formula (XII). After the Mitsunobu reaction, the
reduction reaction is carried out by the well-known reduction method using sodium borohydride. Next, the reaction is

61

EP 1 199 306 A1

carried out in an inactive solvent such as tetrahydrofuran by adding the organic acid such as trifluoroacetic acid, acetic
acid and formic acid to afford the compound of formula (8).

[0254] The reaction temperature is usually 20 °C to the boiling point of the solvent used, preferably, within the range
from 70 to 130 °C.

[0255] The hydrogenation reduction of the compound of formula (8) can be carried out by the method similar to the
method for preparing the compound of formula (lll-ii) from the compound of formula (6) to produce the compound of
formula (lll-iii 1 ).

[0256] The process wherein the compound of formula (lll-iii) can be transformed from the compound of formula (lll-
iii 1 ) is carried out by the protection the amino group using the well-known protective group for amino group such as
tert-butoxycarbonyl group followed by the reaction with R 80 -Ljjj in the presence of an appropriate base such as lithium
hexamethylsilazide and the removal of the protective group for amino group.
[0257] The protection for amino group can be carried out under ordinary condition.

[0258] In the reaction with R 80 -Ljji, to 1 mole of that the compound of formula (lll-iii 1 ), R80" L iii is usually used in 1 mole
or more, preferably 3 mole; the base such as lithium hexamethylsilazide is usually used in 1 or more moles, preferably
3 mole. The reaction temperature is preferably - 78 to 20 °C. The protective group of amino group can be removed
according to the ordinary method.

[0259] The compound of formula (8) can be prepared by reducing the compound of formula (9);

N0 2 (9)

[in the formula, R 40 and R 50 have the meanings given above] to produce the compound of formula (10);

N0 2 (1 0)

[in the formula, R 40 and R 50 have the meanings given above], which is reacted with the compound of formula (11);

R 10a -CH(NH 2 )-T 3 -CH(OH)-R 20a (11)
[in the formula, T 3 , R 10a and R 20a have the meanings given above].

[0260] In the reduction of the compound of formula (9). to 1 mole of the compound of formula (9), sodium borohydride
is used in 0.5 mole preferably in an inactive solvent such as tetrahydrofuran. The reaction temperature is below 0 °C,
preferably -78 °C.

[0261] In the reaction between the compound of formula (1 0) and the compound of formula (11), to 1 mole of the
compound of formula (11), the compound of formula (11) is used in 1 mole or more, preferably 1 mole; and molecular
sieves 4A can be added in 3 times the weight of the compound of formula (1 0).

[0262] The reaction is usually carried out in inactive solvent. The inactive solvent is preferably tetrahydrofuran and
dimethylformamide, and so on.

The reaction temperature is usually 20 °C to the boiling point of the solvent used, preferably, within the range from 1 00
to 120 °C.

[0263] The compound of formula (lll-iv);

62

EP 1 199 306 A1

F?20b

(Ill-iv)

[R 20 b represents optionally substituted lower alkyl group or aralkyl group, R 10 , R 40 and R 50 have the meanings given
above], which is a starting material of the synthetic method A, can be prepared by using the compound of formula

(6) as a starting material as follows.

Synthetic method D

[0264] The compound of formula (Ill-iv) can be prepared by reacting the compound of formula (6) with R20b" OH
(wherein, R 20 b nas the meaning given above) followed by hydrogenation.

[0265] The reaction between the compound of formula (6) and R20b~OH can be carried out by dissolving the com-
pound of formula (6) into R20b"OH, the reaction can be carried out, for example, in case where the compound of formula
(6) is used in 1 mole, the catalytic amount of p-toluenesulfonic acid, preferably 0.1 mole is added.
[0266] The reaction temperature is usually 20 °C to the boiling point of the R20b~OH used(wherein, R 20 b has the
meaning given above), preferably, within the range from 90 to 1 00 °C.

[0267] Next, the compound of formula (Ill-iv) can be prepared by applying hydrogenation under the condition similar
to that of the reaction for preparing the compound of formula (Ill-it) from the compound of formula (6).
[0268] The compound of formula (II) synthesized by the synthetic method A using the compound of formula (Ill-iv)
as a starting material can also be prepared by reacting the compound of formula (Ill-iv 1 );

[in the formula, R 10 , R 40 and R 50 have the meanings given above] with the compound of formula (II) synthesized from
the compound of formula (IV) under condition similar to that of the reaction between the compound of formula (6) and
the R 20b -OH.

[0269] The compound of formula (lll-v);

[in the formula, T 4 represents optionally substituted C^_ 2 alkylene group, R-|0a> ^20a' ^40 anc ' ^50 have the meanings
given above], which is the starting material of the synthetic method A, can be prepared by transforming the compound
of formula (1) to hydrazide followed by the ring closure to obtain the compound of formula (12);

63

EP 1 199 306 A1

HN-NH

N0 2 (12)

[in the formula, R 40 and R 50 have the meanings given above], which is reacted with the compound of formula (1 3);

Ri0a-CH(L a )-T 4 -CH(L a )-R 20a (13)

[in the formula, L a represents halogen atom, T 4 , R 10a and R 20a have the meanings given above] followed by hydro-
genation.

15

Synthetic method E

[0270] The hydrazide compound of formula (1 ) can be prepared by the reaction similar to the reaction between the
compound of formula (1 ) and the compound of formula (2), thus, the hydrazide compound of formula (1 ) can be syn-
20 thesized by activating the compound of formula (1 ) under the similar condition followed by reaction with hydrazine.
[0271] To 1 mole of the compound of formula (1), hydrazine is used in 1 or more mole : preferably 1 to 3 mole.
[0272] The reaction is usually carried out in an inactive solvent. Said solvent includes preferably tetrahydrofuran,
dimethylformamide, and so on.

[0273] The reaction temperature is usually 20 °C to the boiling point of the inactive solvent used, preferably, within
25 the range from 20 to 50 °C.

[0274] The hydrazide obtained above is heated in an inactive solvent such as dimethylformamide to prepare the
compound of formula (12).

[0275] In the reaction between the compound of formula (12) and the compound of formula (13), to the compound
of formula (1 2) of 1 mole the compound of formula (1 3) is 1 mole or slightly more, preferably 1 mole. Said reaction can
30 be carried out in an inactive solvent such as dimethylformamide usually without the addition of base. However, the
reaction can be carried in the presence of tertiary amine such as triethylamine.

[0276] The reaction temperature is usually from room temperature to the boiling point of the inactive solvent used,
preferably, within the range from 1 00 to 120 °C.

[0277] After the completion of the above reaction followed by applying hydrogenation under condition similar to that
35 of the reaction for preparing the compound of formula (lll-ii) from the compound of formula (6), the compound of formula
(lll-iv) can be obtained.
[0278] The compound of formula (lll-vi);

40

45

(lll-vi)

[in the formula, R 10 , R 40 and R 50 have the meanings given above], which is the starting material of the synthetic method
A, can be prepared by using the compound of formula (12) as a starting material as follows.

50

Synthetic method F

[0279] The compound of formula (lll-vi) can be prepared by reacting the compound of formula (12) with the compound
of formula (14);

55

64

EP 1 199 306 A1

[in the formula, L a has the meaning given above] followed by hydrogenation.

[0280] The reaction for preparing the compound of formula (lll-vi) from the compound of formula (12) and the com-
pound of formula (1 4) can be carried out under condition similar to that of the reaction for preparing the compound of
formula (lll-v) from the compound of formula (12).
[0281] The compound of formula (lll-vii);

[in the formula, P 1 represents a protective group of hydroxyl group, R 40 and R 50 have the meanings given above],
which is the starting material of the synthetic method A, can be prepared by applying the following method using the
compound of formula (1) as a starting material.

Synthetic method G

[0282] The compound of formula (lll-vii) can be prepared by synthesizing amide compound from the compound of
formula (1) and diethyl amino malonate followed by cyclization and then decarboxylation under a basic condition to
obtain ester compound, the ester group of which is subjected to reduction to prepare hydroxyl compound, which is
protected by the appropriate protective group and then subjected to hydrogenation.

[0283] The reaction between the compound of formula (1) and diethyl aminomalonatecan be carried under condition

similar to that of the step for preparing the compound of formula (XIX) from the compound of formula (XVII).

[0284] The cyclization reaction is carried out by using an appropriate base, for example, sodium hydride. To 1 mole

of the amide compound, sodium hydride is usually used in 1 mole or more, preferably 1 to 3 mole.

[0285] The reaction is usually carried out in an inactive solvent such as tetrahydrofuran, dimethylformamide and

dimethylsulfoxide. The reaction temperature is usually 0 °C to the boiling point of the inactive solvent used, preferably,

within the range from 20 to 1 00 °C.

[0286] The decarboxylation reaction is carried out in the presence of an appropriate base such as sodium hydroxide.
To 1 mole of the cyclized compound, the base such as sodium hydroxide is usually used in 1 mole or more, preferably
3 to 5 mole. The reaction is usually carried out in an inactive solvent. Said solvent includes preferably alcohols such
as ethanol. The reaction temperature is usually 20 °C to the boiling point of the inactive solvent used, preferably, within
the range from 50 to 1 00 °C.

[0287] The reduction of ester can be carried out according to ordinary reduction method by using, for example,
sodium borohydride. To 1 mole of the ester compound, sodium borohydrade is usually used in 1 mole or more, preferably
3 to 10 mole. The reaction is usually carried out in inactive solvent. Said solvent includes preferably alcohols such as
methanol and ethanol. The reaction temperature is usually 0 °C to 20 °C, preferably 0 °C.

[0288] As to the protective group for newly formed hydroxyl group, the groups described in the synthetic method A
can be used. The preferable examples include tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group and so on. As
to the reaction condition, the generally well-known condition can be applied.

[0289] After the completion of the above reaction followed by applying hydrogenation under the condition similar to
that of the reaction for preparing the compound of formula (lll-ii) from the compound of formula (6), the compound of
°C formula (lll-vii) can be obtained.
[0290] The compound of formula (lll-viii);

R 40 Rso

nh 2 (lll-vii)

50

nh 2 (lll-viii)

65

EP 1 199 306 A1

[in the formula, R-| 0a represents optionally protected saturated or unsaturated hydrocarbon group, R 2 o c represents
hydrogen atom or optionally substituted saturated or unsaturated hydrocarbon group, R 40 and R 50 have the meanings
given above], which is the starting material of the synthetic method A, can be prepared by using the compound of
formula (1) as a starting material as follows.

5

Synthetic method H

[0291] The compound of formula (lll-viii) can be prepared by esterification of the compound of formula (1) followed
by coupling reaction with the compound of formula (1 5);

10

15 n-Bu 3 Sn

[in the formula, R z represents methyl group or ethyl group, R 2 o c nas tne meaning given above] to afford the compound
of formula (16);

20

25

[in the formula, R 2 , R 2 o c ^40 ap d ^so nave the meanings given above], which is converted to the amide compound by
30 using Rioa~NH 2 (wherein, R 10a has the meaning given above) followed by cyclization under an acidic condition, and
then reducing alkoxy group and nitro group respectively.

[0292] The methyl-esterification of the compound of formula (1 ) is carried out in methanol by adding a small amount
of concentrated sulfuric acid under heating according to the generally well-known condition in terms of chemical syn-
thesis.

35 [0293] In the reaction between the above methyl ester and the compound of formula (15). to 1 mole of the methyl
ester, the compound of formula (15) is usually used in 1 mole or more ; preferably 1 to 3 moles and palladium catalyst
such as tetrakistriphosphine palladium is used in preferably 3 to 5 mole%.

[0294] The reaction is usually carried out in an inactive solvent such as tetrahedrofuran. The reaction temperature
is usually 50°C to the boiling point of the solvent used, preferably 70 to 1 00°C.

40 [0295] The amidation between the compound of formula (1 6) and R-|0a~NH 2 can ' 3e carr i e d OLJ t by applying the con-
dition similar to that of the process for preparing the compound of formula (XIX) from the compound of formula (XVII).
[0296] The cyclization reaction of the amide compound obtained above can be usually carried out under an acidic
condition for example, in mixed solvent such as concentrated sulfuric acid and an inactive solvent like ethanol. The
reaction temperature is usually 20 °C to the boiling point of the inactive solvent, preferably 20 to 50 °C.

45 [0297] The reduction of alkoxy group can be carried out for example, by using triethylsilane with the addition of an
appropriate acid.

[0298] To 1 mole of the cyclized compound, triethylsilane is usually used in 1 or more moles, preferably 3 to 5 mole
and the acid added such as the complex of boron trifluoride with ether is used in 1 mole or more, preferably 3 to 5
moles. The reaction is usually carried out in an inactive solvent such as chloroform and dichloromethane. The reaction
50 temperature is usually 0 to 50 °C, preferably 20 °C.

[0299] The reduction of nitro group can be carried out by applying hydrogenation in condition similar to that of the
process for preparing the compound of formula (lll-ii) from the compound of formula (6) to synthesize the compound
of formula (lll-viii).

[0300] According to the synthetic method A, the compound of formula (lll-viii 1 );

55

66

EP 1 199 306 A1

R20CI

[in the formula, R20CI ' s hydrogen atom, R-jQa ^40 anc * ^50 have the meanings given above], which is used as a starting
material for preparing the compound of formula (Il-viii 1 );

(Il-viii 1 )

[in the formula, Ar 0 , R 10a R20d> ^40 anc ' ^50 have the meanings given above], which can also be prepared by applying
the following method.

[0301] The reaction of the compound of formula (lll-vii) with the compound of formula (14) followed by using the
compound of formula (IV) according to the synthetic method A, affords the compound of formula (Il-viii 1 );

(Il-viii")

[in the formula, Ar 0 , Ri 0a , P-h ^40 anc ^ ^50 have the meanings given above]. Next, the protective group of hydroxyl
group is removed to afford the hydroxyl compound, which is converted to methanesulfonate ester and then treated
under a basic condition, finally followed by hydrogenation to obtain the compound of formula (Il-viii 1 ).
[0302] The deprotection of the protective group of hydroxyl group in the compound of formula (Il-viii 1 ) can be carried
out according to the genelally well-known method. For example, in case where the protective group is, for example,
tert-butyldimethylsilyl, the deprotection can be carried out by using concentrated hydrochloric acid in methanol.
[0303] In the methanesulfonation, to 1 mole of the alcohol obtained above, triethylamine is usually used in 1 mole
or more, preferably 1 to 3 mole and methanesulfonic chloride is usually 1 mole or more : preferably 1 to 3 mole. The
base used in the next step, for example, 1 ,8-diazabicyclo[5,4,0]undeca-7-ene (DBU) is usually 1 mole or more, pref-
erably 1 to 3 moles. The reaction is usually carried out in an inactive solvent such as dimethylformamide. The reaction
temperature is usually 0 to 50°C, preferably 0 to 20°C.

[0304] The compound of formula (I Il-viii 1 ) can be prepared by hydrogenation of the compound obtained in the above
reaction under the condition similar to the reaction for preparing the compound of formula (lll-ii) from the compound
of formula (6).

[0305] The compound of formula (lll-ix 1 );

67

EP 1 1 99 306 A1

NH 2 (IM-ix')

"40 R so

[in the formula, R 10c represents optionally substituted saturated or unsaturated hydrocarbon group, R 40 and R 50 have
the meanings given above] and the compound of formula (Ill-ix");

NH 2 (iii-ix")

[in the formula, R 10c > ^Uo anc ' R50 nave tne meanings given above], which are the starting material(s) in the synthetic
method A, can be synthesized according to the following method, using the known compound(s) per se represented
by the formula (1 7);

or the compound(s) prepared from said compound(s) by per se known methods as starting material(s).
Synthetic method I

[0306] The compound of formula (Ill-ix 1 ) and the compound of formula (Ill-ix") can be prepared by the Mitsunobu
reaction between the compound of formula (17) and R 10c -OH [in the formula, R 10c has the meaning given above]
followed by hydrogenation.

[0307] The Mitsunobu's reaction of the compound of formula (1 7) can be carried out by applying the method similar
to that for preparing the compound of formula (XX) from the compound of formula (XII).

[0308] The hydrogenation of the compound obtained in the above reaction, is carried out by applying the condition
similar to that of the method for preparing the compound of formula (lll-ii) from the compound of formula (6) to obtain
the compound of formula (Ill-ix 1 ) and the compound of formula (Ill-ix").
[0309] The compound of formula (lll-x);

68

EP 1 199 306 A1

[in the formula, R-| 0d represents optionally substituted saturated or unsaturated hydrocarbon group, R 40 and R 50 have
the meanings given above], which is the starting material in the synthetic method A, can be prepared by using the
compound of formula (18);

[in the formula, R 10c > ^40 ar| d R50 have the meanings given above], which is the intermediate in the synthetic method
I, according to the following method.

Synthetic method J

[0310] The compound of formula (1 8) is subjected to the reduction to afford the compound of formula (1 9);

[in the formula, R 40 and R 50 have the meanings given above], which is subjected to the Mitsunobu reaction with R 10d
-OH [in the formula, R 10d has the meaning given above] followed by hydrogenation to obtain the compound of formula
(lll-x).

[0311] In the reduction of the compound of formula (1 8), to 1 mole of the compound of formula (1 8), sodium boro-
hydride is usually used in 1 mole or more, preferably 3 to 5 mole. The reaction is usually carried out in an inactive
solvent such as tetrahydrofuran. The reaction temperature is usually 0 to 50 °C, preferably 20 °C.
[0312] The Mitsunobu reaction of the compound of formula (1 9) can be carried out by applying a similar method for
preparing the compound of formula (XX) from the compound of formula (XII).

[0313] The compound of formula (lll-x) can be obtained by applying hydrogenation according to a similar method
for preparing the compound of formula (lll-ii) from the compound of formula (6).

[0314] The compound of formula (1), the compound of formula (5) and the compound of formula (15) can be known
compounds or can be prepared by using the known compound according to the conventional method.
[0315] Next, the synthetic method of the compound of formula (IV). which is another starting material in the synthetic
method A, is illustrated. Specifically, the compound of formula (IV) can be prepared according to the following synthetic
methods from K to M.

Synthetic method K

[0316] Treating the ester compound of formula (20);

R SA A < 20 >

O Ar 0

[in the formula, R 1 represents lower alkyl group, Ar 0 has the meaning given above] with hydrazine followed by reaction
with nitrous acid, the compound of formula (IV);

69

EP 1 199 306 A1

[in the formula, Ar 0 has the meaning given above] can be prepared.

[0317] In transforming reaction wherein the compound of formula (20) is treated with hydrazine followed by reaction
with nitrous acid to obtain the compound of formula (IV), hydrazine is usually used in 1 to 10 mole, preferably 3 to 5
mole to the ester of the compound of formula (20) of 1 mole. In the ne)ct reaction with nitrous acid, to 1 mole of the
ester of the compound of formula (20), sodium nitrite is usually used in 1 to 5 mole, preferably 3 to 5 mole. In the
reaction, to 1 mole of the sodium nitrite acid, 1 N hydrochloric acid is usually used in 1 L to 5 L, preferably 1 L to 3 L.
[0318] The reaction is usually carried out in an inactive solvent.

[0319] Said solvent includes for example, alcohol such as methanol and ethanol in the reaction with hydrazine, and
water, ethers such as tetrehydrofuran and dioxane, halogenated hydrocarbons such as dichloromethane and chloro-
form or the mixed solvent thereof in the reaction with nitrous acid.

[0320] The reaction temperature in the reaction with hydrazine is usually 0 °C to the boiling point of the solvent used,
preferably 20 to 50°C and the reaction time is usually 1 to 48 hours, preferably 5 to 24 hours. The reaction temperature
in the reaction with nitrous acid is usually 0 to 50 °C, preferably 0 to 20 °C and the reaction time is usually 30 minutes
to 5 hours, preferably 30 minutes to 2 hours.

[0321] The compound of formula (20) is the known compound or can be prepared according to the conventional
method for preparing ester.

Synthetic method L

[0322] The compound of formula (IV-i);

no

(IV-i)

FT

[in the formula, R" and R" 1 independently represent optionally substituted saturated or unsaturated 5 or 6 membered
rings, which may contain nitrogen atom taken together with carbon atom to which they bind, respectively.] can be
prepared from the known compound, that is ethyl 1 ,2,4-triazin-5-carboxylate as a starting material, after synthesizing
the compound of formula (21);

O

[in the formula, R" and R 1 " have the meanings given above] according to the synthetic method K.

[0323] The compound of formula (21 ) can be obtained by reacting ethyl 1 ,2,4-triazin-5-carboxylate with thecompound

of formula (22);

[in the formula, R" and R 1 " have the meanings given above].

70

EP 1 199 306 A1

[0324] To 1 mole of ethyl 1 ,2,4-triazin-5-carboxylate, the compound of formula (22) is usually used in 1 or more
moles, preferably 1 to 5 mole. The reaction is usually carried out in an inactive solvent. Said solvent includes for
example, chloroform. The reaction temperature is usually 20 °C to the boiling point of the inactive solvent used, pref-
erably 20 to 70 °C.

5 [0325] The compound of formula (I V-i) can be prepared from the compound of formula (21 ) by applying the method
similar to the method for preparing the compound of formula (IV) from the compound of formula (20) in the synthetic
method K.

Synthetic method M

10

[0326] The compound of formula (IV-ii);

O

15

IV-ii

[in the formula, Ar 10 represents Ar 0 which comprises a substituent of -Sn(n-Bu) 3 ] can be prepared by using the com-
pound of formula (23);

20

R sA Ar (23)

O Ar 10i

25

[in theformula, Ar 101 represents Ar 0 given above, which comprises a substituent of -X 10 (wherein, X 10 is halogen atom),
R 1 has the meaning given above] as a starting material.
[0327] The compound of formula (24);

30

R sAr (24)

O Ar 10

35

[in the formula, Ar 10i and FT have the meanings given above]can be synthesized by reacting the compound of formula
(23) with hexa-n-butylditin using palladium complex such as tetrakistriphenylphosphine palladium as a catalyst accord-
ing to the synthetic method K.

[0328] In the reaction between the compound of formula (23) and hexa-n-butylditin, to 1 mole of the compound of
40 formula (23), hexa-n-butylditin is usually used in 1 or more moles, preferably 1 .5 to 3 moles and tetrakistriphenylphos-
phine palladium is usually used in 0.05 to 0.2, preferably 0.1 mole. The reaction is usually carried out in an inactive
solvent. Said solvent includes for example, dioxane. The reaction temperature is usually 50 °C to the boiling point of
the inactive solvent used, preferably 70 to 130 °C.

[0329] The compound of formula (IV-ii) can be prepared from the compound of formula (24) by applying the method
45 similar to the method for preparing the compound of formula (IV) from the compound of formula (20) in the synthetic
method K.

[0330] Next, the preparation method of the compound of formula (V);

50

55

con 3 (V)

[in the formula, X, Y, Z, R 10 , R 20 , R3o> R 4o> R 50 and " have the meanings given above], which is the starting material

71

EP 1 199 306 A1

in the preparation method B, is illustrated. Specifically, the compound of formula (V) can be prepared according to the
following synthetic method N.

Synthetic method N

5

[0331] The compound of formula (V) can be prepared by converting the compound of formula (25);

10

(25)

C0 2 H

15

[in the formula, X, Y, Z, R 10 , R 20 , R 30 , R50 ancl ~ have the meanings given above] to the corresponding chloride
followed by reaction with sodium azide.

[0332] The reaction for transforming to the chloride of carboxylic acid compound of formula (25) can be carried out
20 by applying the method similar to that for preparing acid halide from the compound of formula (XVIII) under a similar
reaction condition. To 1 mole of acid chloride obtained above, sodium azide is usually used in 1 to 5 mole, preferably
1 to 3 mole. The reaction can be carried out in water or, if necessary, a mixed solvent of water and tetrahydrofuran to
obtain the compound of (V).

[0333] The reaction temperature is usually 0 to 50 °C, preferably 0 to 20 °C and the reaction time is usually 30
25 minutes to 12 hours, preferably 1 to 5 hours.

[0334] The compound of formula (VI), which is another starting material in the preparation method B is a known
compound or can be prepared by applying the conventional method for synthesizing amino compound.
[0335] The IC 50 values for Cdk4 and Cdk6 activities and cell growth inhibition were determined to show the utility of
the compounds in the invention concretely.

30

Cdk4 I nhibory Activity

(1) Preparation of cyclin D1-Cdk4 and cyclin D2-Cdk4

35 [0336] cDNA of Cdk4 and its activator cyclin D1 or D2 was subcloned into a baculovirus-expression vector to make
recombinant baculovirus and then, they are co-infected to insect cell Sf9to express an active complex of cyclin D1 -Cdk4
or cyclin D2-Cdk4. The cells were recovered and solubilized and purified by HPLC columnchromatography (The the
enzyme are EMBO J. vol.15, p. 7060-7069, 1996).

40 (2) Enzyme assay of cyclin D1 -Cdk4 and cyclin D2-Cdk4

[0337] Synthetic peptide, which correspond to the amino acids on the positions of No. 775 to 787 of RB protein (Arg-
Pro-Pro-Thr-Leu-Ser-Pro-lle-Pro-His-lle-Pro-Arg) was used as a substrate. (The EMBO J. vol.15, p. 7060-7069, 1996)
[0338] The reaction was carried out using the modified procedure of Kitagawa's method (Oncogene, vol.7, p.

45 1 067-1 074, 1 992). The volume of the reaction solution was 21 .1 |_il_. The reaction buffer(R buffer) consisted of 20 mM
Tri-HCI buffer(pH7.4)/10 mM MgCI^.S mM 2-mercaptoethanol/1 mM ethyleneglycolbis(p-aminoethylether)-N,N,N',N'-
tetracetic acid(EGTA). Purified cyclin D1 -Cdk4 or D2-Cdk4, 1 00 u,M peptide substrate, 50 jaM unlabeled ATP and ATP
labeled with 1u. Ci y-33P(2000-4000 Ci/mmole) were added to the reaction mixture. The mixture was incubated at 30
°C for 45 min. 1 0 ^il_ of phosphate buffer (350 mM) was added to stop the reaction. The peptide substrate was absorbed

50 to P81 paper and its radioactivity was measured by a liquid scintillation counter. ATP labeled with y-33P was purchased
from Daiich Chemicals, Ltd.

[0339] 1.1 |oL of the solution of test compound in DMSO was added to the reaction mixture, while the addition of
DMSO(1 .1 uL) was used as the control.

[0340] As the typical compounds of the present invention, compounds in working examples No. 131 , 165, 329 and
55 579 were selected to be tested. The IC 50 values for cyclin D1-Cdk4 and cyclin D2-Cdk4 were determined and the
results were shown in the following table.

72

EP 1 199 306 A1

Table 1

Compounds

IC 5O 0iM)

cyclin D1-Cdk4

cyclin D1-Cdk4

Working Example No. 131

0.061

0.019

Working Example No. 329

0.033

Working Example No. 165

0.016

Working Example No. 579

0.011

(+)flavopiridol

0.36

0.056

[0341] It is clear that compounds of the invention have stronger inhibitory activity against cyclin D1 -Cdk4 or cyclin
D2-Cdk4 than that of the known Cdk4 inhibitor (±)flavopiridol.

Cdk6 Inhibiting Activity

(1) Preparation of cyclin D1-Cdk6 and cyclin D3-Cdk6

20

[0342] As the same method of preparing cyclin D1-Cdk4, cDNA of Cdk6 and its activator cyclin D1 or D3 was re-
combined with baculovirus-expression vector to make recombinant baculovirus. This was co-infected to insect cell Sf9
to express an active complex of cyclin D1-Cdk6 or cyclin D3-Cdk6. The cells were recovered and solubilized and
purified by HPLC columnchromatography.

25

(2) Enzyme assay of cyclin D1-Cdk6 and cyclin D3-Cdk6.

[0343] A peptide substrate used for cyclin D1-Cdk6 was synthetic peptide (Lys-Ala-Pro-Leu-Ser-Pro-Lys-Lys-Ala-
Lys) and that used for cyclin D3-Cdk6 was synthetic peptide (Arg-Pro-Pro-Thr-Leu-Ser-Pro-lle-Pro-His-lle-Pro-Arg)
(The EMBO J. vol.15, p. 7060-7069,1 996).

[0344] The reaction was carried out using the modified procedure of Kitagawa's method (Oncogene, vol.7, p.
1067-1074, 1992). The volume of the reaction solution was 21 .1 joL. Purified cyclin D1-Cdk6 in R buffer and 400 u,M
peptide substrate or cyclin D3-Cdk6 and 1 00 jiM pipetide substrate, unlabeled ATP (50 jiM) and 1 u,Ci ATP labeled with
y-33P(2000-4000 Ci/mmole) were added to the reaction mixture. The mixture was incubated at 30 °C for 20 or 45 min.
Then, 10 \xL of phosphate buffer (350 mM) was added to stop the reaction. The peptide substrate was absorbed to
P81 paper and its radioactivity was measured by a liquid scintillation counter.

[0345] 1.1 (_iL of the solution of test compound in DMSO was added to the reaction mixture, while the addition of
DMSO(1 .1 uL) was used as the control.

[0346] As the typical compounds of the present invention, compounds in working examples No. 131, 165, 329 and
579 were selected to be tested. The IC 50 values for cyclin D1-Cdk6 and cyclin D3-Cdk6 were determined and the
results were shown in the following table.

Table 2

Compounds

IC 5O 0iM)

cyclin D1-Cdk6

cyclin D3-Cdk6

Working Example No. 131

0.013

Working Example No. 329

0.065

Working Example No. 165

0.013

Working Example No. 579

0.022

[0347] This results show that the compounds in this invention have a strong inhibitory activities against cyclin
D1-Cdk6 and cyclin D3-Cdk6.

73

EP 1 199 306 A1

Activity of Inhibiting Cell Growth

(1) Method of cell culture

[0348] Clinical separative cancer cells HCT1 1 6 were cultured in Dulbecco 1 modified Eagle's medium with 1 0% Fetal
Bovine Serum ; and clinical separative cancer eel Is MKN-1 were cultured in RPMI1 640 medium added 1 0% Fetal Bovine
Serum. Both cells were cultured at 37 °C, under 5% C0 2 and saturated steam.

(2) Determination of activity of inhibiting cell growth

[0349] The activity of inhibiting cell growth was measured using the modified method of Skehan's method (J.Natl.
Cancer Inst. Vol.82, p.1 107-11 12, 1990), and so on. One hundred j-il_ each of the culture medium containing 1x10 3
HCT1 1 6 or MKN-1 as living cells was pipetted to 96-well dish and cultured over night. On the next day, DMSO solution
of compounds No. 131 and ( + )flavopiridol were diluted with DMSO serially. Then, the diluted compounds or DMSO
as the control, was added to the medium. One hundred j_il_ of the medium added with the diluted drug solutions or
DMSO was added to the cells cultured in 96-well dish, and was incubated for further 3 days.

[0350] To each well, 50 [iL of trichloroacetic acid (50%) was added to fix the cells. The cells were stained using 0.4%
sulforhodamine B. Sulforhodamine B was extracted with 1 0mM tris buffer, and the optical density at 560nm was com-
pared with that of control at 450 nm. The results of IC 50 values of the compound in working example No. 131 and (±)
flavopiridol were shown in the following table.

Table 3

Compounds

IC 50 0iM)

IC 50 OiM)

HCT116 Cell

MKN-1 Cell

Compound in Working Example No. 131

0.013

0.10

(±)flavopiridol

0.15

0.87

[0351] This results show that the compounds in the invention have a stronger activity of inhibiting cell growth in
compared with that of the known compound, (±)flavopiridol which has an activity of inhibiting Cdk. Therefore, they may
be used as antitumor agent.

[0352] The compounds in the invention may be used in cancer treatment for example the treatment of human colon
cancer.

[0353] When used as antitumor agent, the compounds may be used in the form of pharmaceutically acceptable salts
like salts with metals such as sodium, potassium, and so on.

[0354] The salts, which can be pharmaceutically acceptable, can be synthesized by combining the methods generally
used in organic chemistry, for example, the neutralization titration of the free form of the compounds in the present
invention using alkaline solution.

[0355] When used as an antitumor agent, the compounds in the invention may be administrated in any formulation,
for example, oral formulations such as tablets, capsules, powders, granules or sterilized parenteral formulations such
as solutions, suspensions, and so on.

[0356] In cases of solid formulation, compounds in the invention may be prepared directly as the forms of tablets,
capsules, powders, or prepared with proper additives. As the additives, there can be mentioned the additives generally
used in preparing the above-mentioned formulations, for example, sugars, like dextrose, lactose, and so on, starches,
like maize, wheat, rice, and so on, aliphatic acids like, steric acid, and so on, inorganic salts, like sodium metasilicate,
magnasium aluminate, anhydrous calcium phosphate, and so on, synthetic polymer, like polyvinylpyrrolidone, poly-
alkyleneglycol, and so on, salts of aliphatic acid, like calcium stearate, meganisium stearate, and so on, alcohols, like
stearylalcohol, benzyl alcohol, and so on, synthetic cellulose derivatives, like methylcellulose, carboxyl methylcellulose,
ethylcellulose, hydroxy propyl methylcellulose, and so on, others, like water, zeratine, tark, plant oil, gum Arabic, and
so on.

[0357] In the solid pharmaceutical composition of the invention, such as tablets, capsules, granules, powders, and
so on, the amount of active ingredient is usually 0.1 to 1 00% by weight, or preferably 5 to 1 00% by weight of total weight
of the composition. In cases of the liquid pharmaceutical composition of the invention, water, alcohols or plant oil, like
soybean oil, peanuts oil, sesame oil, and the like may be used as proper additives to prepare suspensions, syrups,
injections, and so on.

[0358] When administrated orally as intramuscular injection, intravenous injection or subcutaneous injection, the
examples of proper solvents may be the following substances or their mixture; distilled water for injection, lidocaine

74

EP 1 199 306 A1

hydrochloride aq.solution(for intramuscular injection), physiological saline, dextrose, ethanol, liquids for intravenous
injection(like solution of citric acid, sodium citrate, and so on), electrolyte solutions(for intravenous drip infusion, intra-
venous injections), and so on.

[0359] When used as injections, the above-mentioned substances or their mixture may be used by dissolving prior
5 to use, or used by dissolving the powder or with proper additives before use. The content of active ingredient in these
injections is usually in the range of 0.1 to 10% by weight, or preferably 1 to 5%. When used as solutions such as
suspensions or syrups, the content of active ingredient can be 0.5 to 1 0% by weight.

[0360] As a practical matter, the preferable dosage of the present invention can be determined according to the kind
of the compounds, the kinds of contents used in formulation, frequency of the use, specific position to be treated and
10 the situation of the patients. For example, oral dosage for an adult may be 10 to 500 mg/day and parenteral dosage
like injection may be 1 0 to 1 00 mg/day. Single dose or multiple dose of 2 to 5 times a day may be applied, while times
of administration may be different depending on administration routs and situation of the patients.

The best Mode for Carrying out the Invention

15

[0361] Hereunder, the present invention is illustrated in more detail by the following Reference Examples and Ex-
amples. However, the scope of the present invention is not to be considered to be restricted to the present embodiment.
[0362] In the Thin Layer chlomatography in the Examples and Reference Examples, the Silica gel 60 F 25 4 plates man-
ufactured by Merck & Co., were used as the TLC-plate, and as the detection method, the UV-detector was adopted.

20 As silica gel for the column chlomatography, Wako gel TM C-300 or C-200 manufactured by Wako Pure Chemicals,
Ltd. was used. As HPLC, HP1100 series manufactured by Heulet Packard was used. MS spectrum was measured by
JMS-SX102A (JEOL) orQUATTRO ll(Micro Mass). NMR (Nuclear Magnetic Resonance) spectrum was measured by
a Gemini-200(200MHz, Varian), Gemini-300(300MHz, Varian) and VXR-300(300MHz, Varian), using TMS(tetra methyl
silan) for deuterated chloroform solutions, and methanol for deuterated methanol as internal standard. All 8 values

25 were in ppm.

Abbreviations used in NMR have the following meanings;
[0363]

30

s : singlet
d : doublet
dd : double-doublet
t : triplet
35 dtdouble triplet

q : quartet
m : multiplet
br : broad

J : coupling constant
40 Hz : Hertz

CDCI 3 :deuterated chloroform

D 2 0 : deuterium oxide

DMSO-d 6 : deuterated dimethylsulfoxide

CD 3 OD : deuterated methanol

45

Abbreviations used in Reaction formulas or the like have the following meanings;
[0364]

50 Ac : Acetyl group

Et : Ethyl group

n-Bu : n-Butyl group

Bn : Benzoic group

n-Pr:n-propyl group
55 i-Pr:iso-propyl group

Me : Methyl group

Ph : Phenyl group

Py : Pyridine group

75

EP 1 199 306 A1

TEA : Triethylamine

[0365] Examples of the compounds in the present invention are concretely shown in the following tables.

Table 4

Example

Ring structure formed by R lt R 2 and X taken together Ar

R.

1

O X)

H

H

H

2

H

H

H

3

o x>

H

H

H

4

H

H

H

5

O JO

H

H

H

6

o ^?

Urn

H

H

H

7

o ^9

H

H

H

8

o ^?

MW«t

H

H

H

9

o ^?

N M |

H

H

H

76

EP 1 199 306 A1

77

EP 1 199 306 A1

78

EP 1 199 306 A1

79

EP 1 199 306 A1

Table 8

10

(la)

15

Example Ring structure formed by R,, R 2 and X taken together Ar

R.

43

CMjCOjEt

H

H

H

20

25

30

35

40

45

50

44

H

OHtCOjB)

H

H

45

o

Ph

H

H

H

46

if"""-!

Ptl(4-Cf)

H

H

H

47

o

SO yPh |4-MO|)

H

H

H

48

o

H

H

H

49

o

H

H

H

50

o

H

H

H

51

o

H

H

H

52

o

H

H

H

53

o

H

H

H

55

80

EP 1 199 306 A1

Table 9

(la)

Example Ring structure formed by R 1( R 2 and X taken together

or chemical structures of the substituents

Ar

54

55

56

57

58

59

60

61

64

"0

R 1= H ; R 2 =0

R^Me ; R 2 = 0

R^Et ; R 2 =0

R,=n-Pr ; R 2 =0

R,=i-Pr ; R 2 =0

R^n-Bu ; R 2 =0

Rj=<CH 2 ) 4 OH; R 2 =0

62 R^CHjCHCCHjOH^ ; R 2 =0

63 R^CHzCOOEt ; R 2 =0

R^Bn ; R 2 =0

H

H

H

H

H

H

H

H

H

H

H

Br

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

81

EP 1 199 306 A1

Table 10

Example

Chemical structures of the substttuents

Ar

Re

Rb

65

R,=(CH 2 ) 2 Ph ; R 2 =0

H

H

H

66

R,=CH 2 Ph(2-NH 2 ) ; R 2 =0

H

H

H

67

R,=CH 2 Ph(3-NH 2 ) ; R 2 =0

H

H

H

63

R 1 =CH 2 (2-Py) ; R 2 =0

H

H

H

69

R^CHzO-Py) ; R 2 =0

H

H

H

70

R,=CH 2 (4-Py) ; R 2 =0

H

H

H

71

R t =CH 2 Ph(4-MeOCO) ; R 2 =0

H

H

H

72

R l =2-cyclohexerr*1-yl ; R 2 =0

H

H

H

73

R^yclohexylmethyl ; R 2 =0

H

H

H

74

R^N-methylpiperidin-4-yl ; R 2 =0

H

H

H

82

EP 1 199 306 A1

Table 11

55

83

EP 1 199 306 A1

Table 12

55

84

EP 1 199 306 A1

Table 13

10

(la)

Example Ring structure formed by R t . R 2 and X taken together Ar R a

15

101

O

N -4

(CMs^HHCHjCpyBn

H

H

H

102

O

N —

H

H

H

20

103

o

N /

1

tCH t ) a H>CH r 2-Pr

H

H

H

25

104

o

H

H

H

30

105

O

N 4

tCMjtyNMCHr^-Py

H

H

H

106

O

N 4

H

H

H

35

107

H

H

H

40

108

H

H

H

109

H

H

H

45

110

(CHjyttlCOlOltbCHt

H

H

H

50

111

H

H

H

55

85

EP 1 199 306 A1

10

15

20

30

35

40

45

Table 14

H

T Ar (la)
O

Ex ample Ring structure formed by R 1t R 2 and X taken together Ar R,

112 \ 7 H H H

113 V " 7 H H H

114 \ 7 H H H

(CHj),NH&OjPtl

o ^

N — " ■ # ICMJU

25 115 \7 y H H H

116 \ 7 ^ H H H

117 \ 7 V H H H

118 \ 7 \L^- H H H

119 \ 7 vL/- H H H

120 \ 7 vL H H H

121 \ 7 1_ H H H

50

55

86

EP 1 199 306 A1

Table 15

10

50

55

H

T Ar (la)
O

Example

Wnfl structure formed by ft u Ra and X taken together

Ar

122

w

■ ■

H

H

H

15

123

H»C(H01HC ^^-V

H

H

H

124

X

H

H

H

20

125

CHjOM
N /

H

H

H

25

126

CHjNH,

H

H

H

127

Cr"

H

H

H

30

128

H

H

H

129

o

H

H

H

35

130

H

H

H

131

Ti

h

H

H

40

132

X3

H

H

H

Notes: l . The symbol ■ * " in *y> means the position of anneiation or the position of ring condensation.

45

Accordingly the product of Example 54 means «-<>^a s v «l

T O

2. The symbol "'"in means the position of annulatkxi or the position of ring condensation.

Accordingly the product ol Example 79 means "^^f^^^t^

87

EP 1 1 99 306 A1

Table 16

x— :

> \ 3H H
<J O

Example Y R i R 2 R 3

or ring structure formed by X t Z, R 1t R 2
and/or R 3 taken together

A r

R* i

133 CO

134 CO

H

same as the above

same as the above

H

Y

R'

H

H

135 CO

same as the above

same as the above

*o H

136 CO

137 CO

138 CO

139 CO

140 CO

141 CO

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

^JI — cp

same as the above "^S

same as the above

c5P
op

OH

same as the above

same as the above

same as the above

H

H

H

H

H

H

142 CO

143 CO

same as the above

same as the above

same as the above

same as the above

H

H

88

EP 1 199 306 A1

Table 17

' H H

Example Y

R i R 2 R 3

or ring structure formed by X, Z, R ( , R 2
and/or R 3 taken together

A r

144 CO

145 CO

146 CO

147 CO

148 CO

149 CO

150 CO

151 CO

152 CO

H

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

R'

H

H

H

H

H

H

H

H

H

153 CO

same as the above

same as the above

H

154 CO

same as the above

same as the above

H

89

EP 1 1 99 306 A1

Table 18

R ,1 R.

3H H

N T N ^r
O

Example Y R i ^2 ^3 Ar

or ring structure formed by X, Z, R,, R 2
and/or R 3 taken together

155 CO

155 CO

157 CO

158 CO

159 CO

160 CO

161 CO

162 CO

163 CO

164 CO

165 CO

H

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

Vir.

S 1

n 1

same as the above

same as the above

same as the above

same as the above

HO

HO

same as the above \
same as the above ^< \

same as the above

same as the above

same as the above

same as the above

R"

H

H

H

H

H

H

H

H

^3

Xn>, h

90

EP 1 199 306 A1

Table 19

X Z-R 3H H

Example Y

R i R 2 R 3
or ring structure formed by X, Z, R 1f R 2
and/or R 3 taken together

A r

166 CO

167 CO

H

same as the above

same as the above

R'

H

H

168 CO

same as the above

same as the above

X)

jHl

169 CO

same as the above

same as the above 1 N —

H

170 CO

171 CO

172 CO

173 CO

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

H

H

H

H

174 CO

same as the above

same as the above NH

H

175 CO

same as the above

same as the above

H

176 CO

same as the above

same as the above

H

91

EP 1 199 306 A1

Table 20

X-Z-R
Y

f ^ "3H H

"At

Example Y

R i R 2 R 3
or ring structure formed by X. Z, R t , R 2
and/or R 3 taken together

A r

R* t

R '

177 CO

178 CO

179 CO

180 CO

181 CO

182 CO

H

same as the above

same as the above

same as the above

same as the above

same as the above

R':

same as the above

same as the above

same as the above

same as the above

H

H

T>0

H

H

same as the above "^^f^N^^y ^

183 CO

same as the above

same as the above

H

184 CO

same as the above

same as the above

H

185 CO

same as the above

same as the above

H

186 CO

187 CO

same as the above

same as the above

same as the above

same as the above Xt ^

r

H

H

92

EP 1 1 99 306 A1

Table 21

R .1 Ro

X Z-R 3H H

o

Example Y

R i R 2 R 3
or ring structure formed by X, Z, R,, R 2
and/or R 3 taken together

A r

R' i

188 CO

189 CO

190 CO

191 CO

same as the above

same as the above

same as the above

ni

n 1

same as the above

same as the above

same as the above

HN.

R'

H

H

H

H

192 CO

193 CO

194 CO

195 CO

same as the above

same as the above

same as the above

same as the above

same as the above )— \ H

same as the above N ) — y H

same as the above ' — / ) — v H

HlO

same as the above

"oO H

196 CO

same as the above

same as the above

H

197 CO

same as the above

same as the above

H

198 CO

same as the above

same as the above

93

EP 1 199 306 A1

Table 22

x

Y

3 H

H
N

Example Y

R i R 2 R 3
or ring structure formed by X, Z, R 1t R 2
and/or R 3 taken together

A r

R' i

199 CO

200 CO

201 CO

same as the above

same as the above

H

R' 2 "t>

same as the above

same as the above

R'

H

H

H

202 CO

same as the above

same as the above vC N '

H

203 CO

204 CO

same as the above

same as the above

same as the above "^^J^-^^C^ H

same as

the above ^XjN~O0 H

205 CO

206 CO

same as the above

same as the above

same as

the above>Q^jQ H

same as the abave^^\f-(^\^ H

207 CO

same as the above

same as the above

o

H

208 CO

209 CO

same as the above

same as the above

same as the above

same as the above

b H

94

EP 1 1 99 306 A1

Table 23

R 1 ,Ro

X 2 R 3H H

O

Example Y

R i R 2 R 3
or ring structure formed by X, Z, R 1t R 2
and/or R 3 taken together

A r

R' i

210 CO

211 CO

H V^R' f

same as the above

n 1

same as the above

R *

H

H

212 CO

same as the above

same as the above

213 CO

214 CO

215 CO

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

xk

H

H

H

216 CO

same as the above

same as the above

H

217 CO

218 CO

same as the above

same as the above

same as the above

same as the above

H

H

219 CO

same as the above

same as the above

H

220 CO

same as the above

same as the above

H

95

EP 1 199 306 A1

Table 24

J* ? ^3H H

Example Y R 1 R 2 R 3

or ring structure formed by X. 2, R,, R 2
and/or R 3 taken together

A r

R ' 1

R*

221 CO

222 CO

H

same as the above

same as the above

Xr*0

H

H

223 CO

224 CO

225 CO

226 CO

same as the above

same as the above

same as the above

same as the above

same as the above -^C~?NH

same as the above

same as the above \ 7

same as the above

H

H

H

H

227 CO

228 CO

229 CO

same as the above

same as the above

same as the above

same as the above ^X^^^n

HlO

same as the above

same as the above

H

H

H

230 CO

same as the above

same as the above

H

231 CO

same as the above

same as the above / j — y

96

EP 1 199 306 A1

Table 25

X \ R 3H H

Example Y

R i R 2 R3
or ring structure formed by X, Z, R, , R 2
and/or R 3 taken together

Ar

R ' 1

232 CO

233 CO

H

same as the above

same as the above

H

H

234 CO

235 CO

same as the above

same as the above

same as the above

same as the above

H

^>>> H

236 CO

same as the above

same as the above

H

237 CO

238 CO

same as the above

same as the above

same as the above

HN^N

239 CO

240 CO

same as the above

same as the above

same as the above <w >=\ H
same as the above ^n^J^ H

241 CO

same as the above

same as the above

"D»-\-NH 2 H

242 CO

same as the above

same as the above

97

EP 1 1 99 306 A1

Table 26

R 1 ,Ro

X 2 R 3H H

Example Y

R i R 2 R 3
or ring structure formed by X, Z, R,, R 2
and/or R 3 taken together

A r

R* i

243 CO

244 CO

H

same as the above

same as the above

R'

H

H

245 CO

246 CO

same as the above

same as the above

same as the above

same as the above

"Orb

H

H

247 CO

248 CO

249 CO

250 CO

251 CO

252 CO

253 CO

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

H

H

H

H

H

H

98

EP 1 199 306 A1

Table 27

x

Y

R

' z r^3H H

T Ar

o

Example Y R i R 2 R 3

or ring structure formed by X, Z, R 1f R 2
and/or R 3 taken together

A r

R * x

254 CO

255 CO

same as the abova

H

R'.

same as the above

R'

H

H

256 CO

same as the above

same as the above

xro

H

257 CO

same as the above

same as the above

TTO

H

258 CO

same as the above

same as the above

H

259 CO

same as the above

same as the above

H

260 CO

261 CO

262 CO

263 CO

264 CO

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above^X^jll^O

same as the above

10

same as the above

same as the above

^3

H

H

H

H

H

99

EP 1 199 306 A1

Table 28

x

V

Z «3H H

Y Ar

o

Example Y

R a R2 R3
or ring structure formed by X, Z, B u R 2
and/or R 3 taken together

A r

R' 1

265 CO

H X)

R'

H

266 CO

same as the above

— "^b

H

267 CO

268 CO

269 CO

same as the above

same as trie above

same as the above

same as the above

same as the above

same as the above

H

H

H

270 CO

271 CO

272 CO

273 CO

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

x9

H

H

H

H

274 CO

same as the above

same as the above

H

275 CO

same as the above

same as the above

H

100

EP 1 1 99 306 A1

Table 29

Example Y

R i R 2 R 3
or ring structure formed by X, Z, R,, R 2
and/or R, taken together

A r

R ' !

R'

276 CO

277 CO

278 CO

279 CO

H

same as the above

same as the above

same as the above

same as the above^^T^^

same as the above

H

same as the above y^.

H

H

H

H

280 CO

281 CO

282 CO

283 CO

284 CO

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

9

same as the above ^^ig^Y^^

same as the above

X

H

same as the above

xo

H

same as the above

x

no

H

H

H

H

H

285 CO

286 CO

same as the above

same as the above

same as the above •^n'^Y^*N

H KJ

same as the above ^^N""^Tf n

H

H

101

EP 1 199 306 A1

Table 30

X-i Z-R 3H H

Y Ar
o

Example Y

R i R 2 R 3
or ring structure formed by X, Z, R,, R z
and/or R a taken together

A r

R* i

287 CO

288 CO

H

same as the above

same as the above

O

289 CO

same as the above

same as the above

H

290 CO

291 CO

same as the above

same as the above

same as the above

same as the above

r

H

H

292 CO

same as the above

same as the above

H

293 CO

same as the above

same as the above

H

294 CO

same as the above

same as the above^^Jl?^^ H

295 CO

same as the above

same as the above

-^^OH H

296 CO

same as the above

same as the above

H

297 CO

same as the above

same as the above L H

OH

102

EP 1 199 306 A1

Table 31

x

V

f V R 3 H H

Example Y R 1 R 2 R 3

or ring structure formed by X, Z. R, , R 2
and/or R 3 taken together

A r

R" i

298 CO

H

r 4 -^Osj H

R"

H

299 CO

same as the above

same as the above

H

300 CO

301 CO

302 CO

303 CO

304 CO

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above \

same as the above

same as the above

same as the above

same as the above

HO> H

H

H

H

H

H

305 CO

same as the above

same as the above

Me

H

306 CO

same as the above

same as the above

H

307 CO

same as the above

same as the above

H

308 CO

same as the above

same as the above

H

103

EP 1 1 99 306 A1

Table 32

X

Y

■ \ R 3H H

XTY >r

Example Y

R i R 2 R 3
or ring structure formed by X, Z, R,, R 2
and/or fl 3 taken together

A r

R ' i

R '

309 CO

310 CO

311 CO

312 CO

313 CO

314 CO

315 CO

H

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

H

same as the above *^^tj

H

same as the above*

same as the above

same as the above

same as the above

same as the above

H

H

no h

O

316 CO

same as the above

same as the above

.0

317 CO

318 CO

319 CO

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

pro

o

104

EP 1 199 306 A1

Table 33

x

Y

R

; % ^3H H

Example Y

R ! R 2 R 3

or ring structure formed by X, Z, R t , H 2
and/or R 3 taken together

At

R'

320 CO

321 CO

322 CO

H

same as the above

same as the above

same as the above

same as the above

H

o

6

323 CO

same as the above

same as the above x^v^NHj

H

324 CO

same as the above

same as the above ^\^-NMz

H

325 CO

same as the above

same as the above

H

326 CO

same as the above

same as the above

H

327 CO

328 CO

same as the above

same as the above

same as the

h rr

same as ihe above c^n/

cTo

H

329 CO

same as the above

same as the above

H

H

330 CO

same as the above

same as the above

H

H

105

EP 1 199 306 A1

Table 34

x

Y

; \ R 3H H

Example Y

R l R 2 R 3
or ring structure formed by X, Z, R, , R 2
and/or R 3 taken together

A r

R ' i

R'

331 CO

H

R'.

H

332 CO

same as the above

same as the above ^-^fC^i H

H

333 CO

same as the above

same as the above jJ^^ffO^Q H

334 CO

same as the above

same as the above j ^^.j(^V'Nhfe H

335 CO

same as the above

same as the above

H

336 CO

337 CO

338 CO

same as the above

same as the above

same as the above

same as the above

H
N

same as the above

H

H

H

same as the above

339 CO

same as the above

same as the above ^^n^JQL - H

XT

340 CO

same as the above

same as the above

H

341 CO

same as the above

same as the above

H

106

EP 1 1 99 306 A1

Table 35

X

t

Y

■ f \ R 3H H

Example Y

R i R 2 R 3

or ring structure formed by X, Z, R 1( R 2
and/or R 3 taken together

A r

R'

342 CO

343 CO

344 CO

345 CO

346 CO

H

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

H

H

H

H

H

.N

H

H

H

H

H

347 CO

same as the above

same as the above

H

H

348 CO

349 CO

same as the above

same as the above

same as the above

same as the above

V?

H

H

350 CO

351 CO

352 CO

same as the above

same as the above

same as the above

same as the above

same as the above

H

same as the above

H

H

H

107

EP 1 1 99 306 A1

Table 36

X z R 3H H

o

Example Y R i R 2 R 3

or ring structure formed by X, Z, R,. R 2
and/or R 3 taken together

A r

R' i

353 CO

354 CO

H

same as the above

H

R' 2

same as the above

R'

H

H

355 CO

same as the above

same as the above

H

356 CO

same as the above

same as the above ^"v^N^C^

H

357 CO

same as the above

same as the above

H

X5l

H

358 CO

359 CO

360 CO

same as the above

same as the above

same as the above

same as the above

same as the above

same as the above

S 0

H

H

H

361 CO

same as the above

same as the above

H

362 CO

same as the above

same as the above

CI

H

363 CO

same as the above

same as the above

H

108

EP 1 1 99 306 A1

Table 37

X Z-R 3H H

Example Y

R ] R 2 ^ 3

or ring structure formed by X, Z t R t , R 2
and/or R 3 taken together

A r

364 CO

H

H

R '

H

365 CO

same as the above

same as the above

H

366 CO

same as the above

same as the above

H

367 CO

same as the above

same as the above

H

368 CO

same as the above

same as

, he above ^J^Q-^ H

369 CO

same as the above

same as

the above ^JIX^ 00 ^ H

370 CO

same as the above

same as the above

nj^^y h

371 CO

same as the above

same as the above ^JJjQ' 0 ^^^ H

372 CO

same as the above

same as the above n^O^°^^

H

373 CO

same as the above

same as the above

.\LO < ^ j0i H

374 CO

same as the above

same as the above j^^*^^^ ^

109

EP 1 199 306 A1

Table 3 8

Ri
x

V

,R2

. Z-Hsh H

Example Y R i R 2 R 3

or ring structure formed by X, Z. R,, R 2
and/or R a taken together

A r

R ' i

R*

375 CO

376 CO

H

same as the above

same as the above

H

H

377 CO

same as the above

same as the above

cr 0

H

378 CO

same as the above

same as the above ^-v^l^CX

H

379 CO

same as the above

same as the above

H

380 CO

same as the above

same as the above

H

381 CO

same as the above

same as the above .^-^L-O-i

H

382 CO

same as the above

same

as the above .^^K^O-q^iL

H

383 CO

384 CO

same as the above

same as the above

same as the above

same as the above

H

H

385 CO

same as the above

same as the above ✓^K^O- n -^lQ

H

110

EP 1 199 306 A1

Table 39

R 1 ,Ro

X Z-R 3H H

VV N Y^Ar
kj 1 O

Example Y

R i R 2 R3
or ring structure formed by X, Z, R, f R 2
and/or R 3 taken together

A r

R' 1

R'

386 CO

H

FT:

ZXXaJO H

387 CO

same as the above

same as the above ^-JJ^-Oq--^

H

388 CO

same as the above

same as the above

Hj^—Q H

389 CO

same as the above

same as the above H

390 CO

same as the above

same as the above H

N
H

391 CO

same as the above

same as the above H

H

392 CO

same as the above

same as the above H

H

393 CO

same as the above

same as the above H

NH

394 CO

same as the above

same as the above H

395 CO

same as the above

same as the above H

H

396 CO

same as the above

same as the above H

H

111

EP 1 199 306 A1

Table 40

v; \ 3 H H

VyVSt

k^J o

Example Y

R i R 2 R 3
or ring structure formed by X, Z, R,, R 2
and/or R 3 taken together

A r

R * i

397 CO

H

R' ;

H

R*

H
N

398 CO

same as the above

same as the above H

399 CO

same as the above

same as the above H

400 CO

same as the above

same as the above C O 2 M e

401 CO

same as the above

same as the above C O 2 M e

402 CO

403 CO

same as the above

same as the above

R'i

same as the above

H

o.

H

H

404 CO

405 CO

406 CO

407 CO

FT

H

same as the above H

same as the above H

same as the above H

EP 1 199 306 A1

Table 41

X Z-R 3H H

Example Y Ri "2 R 3

or ring structure formed by X, Z, R,, R 2
and/or R, taken together

Ar

R' 1

R'

408 CO

H

R' ;

H

H

409 CO H

OH

H same as the above H

H

410 CO Me same as the above H same as the above H

H

411 CO

same as the above H same as the above H

H

412 CO

same as the above hi same as the above hi

H

413 CO

same as the above H same as the above H

H

414 CO

same as the above H same as the above H

H

415 CO

nc

same as the above H same as the above H

H

416 CO

same as the above H same as the above H

H

417 CO

same as the above H same as the above H

H

418 CO

same as the above H same as the above H

H

EP 1 1 99 306 A1

Table 42

R .1 ,Ro
X— Z-R 3H H

kJ 1 o

Example Y

419

R i R 2 R 3

or ring structure formed by X, Z, R„ R 2
and/or R 3 taken together

A r

OH

H

R'.

H

R '

H

420 CO

F

same as the above H same as the above H

H

421 CO

same as the above H same as the above H

H

422 CO

423 CO

Ok

same as the above H same as Vie above H

same as the above H same as the above H

H

H

424 CO Me

Me

H same as the above H

H

425 CO

\

same as the above H same as the above H

H

426 CO

same as the above H same as the above H

H

427 C

same as the above H same as the above H

H

428 CO

429 CO

same as the above H same as the above H

same as the above H same as the above H

H

H

EP 1 1 99 306 A1

Table 43

R ,1 ,FU

X Z-R 3H H

Example Y Ri R 2 R3 Ar R'i R'

or ring structure formed by X, Z, R„ R 2
and/or R 3 taken together

430 co *^£y H s ^ n * H H

435 CO

431 CO A 7 H same as the above H H

432 CO KJ^*K H same as the above H H

M-7

433 CO HO \ / H same as the above H H

434 CO \ / H same as the above H H

^^X^-°x H same as the above H H

436 CO r \ r> H same as the above H H

437 CO H same as the above H H

438 CO ^ OH H same as the above H H

439 CO /^N, \ H same as the above H H

440 CO ^ * H same as the above H H

EP 1 1 99 306 A1

Table 44

R .1 ,Ro
X— Z-R 3 H |_|

Y Ar

o

Example Y R i R 2 R 3

or ring structure formed by X, Z, R,, R z
and/or R a taken together

A r

441 CO

H

R':

R' i

H

R '

H

442 CO m as (tie above

H same as the above H

H

443 CO same as the above

H same as the above H

H

444 CO same as trie above

✓Ok H

same as the above H

H

445 CO same as the above

H same as the above H

H

446 CO same as the above ^o^X^ H

same as the above H

H

447 CO same as the above

same as the above H

H

443

C O same as the above ^^J^) H same as the above H

H

449 CO

H same as the above H

H

450 CO

451 CO

H

H same as the above H

H same as the above H

H

H

EP 1 199 306 A1

Table 4 5

R ,1 R

x-z-f3 3H H

YyY^

R

R

Example Y R 1 ^ 2 IV 3

or ring structure formed by X, Z, R,, R 2
' and/or R 3 taken together

A r

R' i

452 CO

455 CO

H

453 CO & A H

454 co 1£, h

H

H

H same as the above H

H same as the above H

H same as the above H

R'

H

H

456 CO Me

H

H same as the above H

H

457 CO

458 CO

\ H

\

\

H same as the above H

H same as the above H

H

H

459 CO

H

H same as the above H

H

460 CO

461 CO

462 CO

H

H

H

H same as the above H

H same as the above H

H same as the above H

H

H

H

EP 1 199 306 A1

Table 46

x

Y

; Z \ ^3H H

Example Y

R i R 2 R 3
or ring structure formed by X, Z, R 1r R 2
and/or R 3 taken together

A r

R' i

R'

463 CO

464 CO

465 CO

466 CO

467 CO

468 CO

469 CO

470 CO

471 CO

472 CO

473 CO

H

CI

H

H

H

H

VP

H XX

n 1

H

H same as the above H

H same as the above H

H same as the above H

H same as the above H

H same as the above H

H same as the above H

H same as the above H

H same as the above H

H same as the above H

H same as the above H

H

H

H

H

H

H

H

H

H

H

118

EP 1 1 99 306 A1

Table 47

X-Z-R 3H H

Example Y Ri R2 R 3

or ring structure formed by X, Z, R,, R 2

A r

and/or R 9 taken together

474 CO

475 CO

476 CO

H

H same as the above

H same as the above

477 CO

X?

H same as the above

478 CO

H same as the above

479 CO

480 CO

481 CO

H same as the above

H same as the above

H same as the above

482 CO

483 CO

484 CO

O 5

H same as the above

H same as the above

H same as the above

EP 1 199 306 A1

Table 48

Ri R

3H H

o

Example Y R i ^2 R 3 Ar R'i

or ring structure formed by X T 2. R„ R 2

and/or R 3 taken together

485 CO

486 C

^D 3

H

H

H same as the above H

R'

H

H

487 C

H same as the above M

H

488 CO

H same as the above H

H

489 CO

490 CO

491 CO

H same as the above H

H same as the above H

H same as the above H

H

H

H

492 CO

493 CO

494 CO

495 CO

N

H same as (he above H

H same as the above H

H same as the above H

H same as the above H

H

H

H

H

120

EP 1 1 99 306 A1

Table 49

R >1 ,Ro

f 4 "3H H

6

Example Y R i R 2 R 3

or ring structure formed by X, Z, H u R 2
and/or R 3 taken together

A r

496 CO

497 CO

498 CO

499 CO

H

H

H same as the above H

H same as the above H

H same as the above H

R'

H

H

H

H

500 CO

501 CO

502 CO

503 CO

504 CO

505 CO

506 CO

o

H same as the above H

H same as the above H

H same a3 the above H

H same as the abcve

H same as the above same as the above

H same as the above same as the above

H same as the above same as the above

H

H

H

H

H

H

H

121

EP 1 199 306 A1

Table 50

X— Z-R 3H H

T Ar
o

Example Y

R l R 2 R 3
or ring structure formed by X, Z, R,, R 2
and/or R 3 taken together

A r

R ' ,

R*

507 CO

508 CO

509 CO

510 CO

H

H

H same as the above same as the above H

H same as the above same as the above H

H same as the above same as the above H

511 CO

H same as the above same as the above H

512 CO

513 CO

514 CO

515 CO

516 CO

H same as the above same as the above H

H same as the above same as the above H

H same as the above same as the above H

H same as the above same as the above H

H same as the above same as the above H

517 CO

H same as the above same as the above H

122

EP 1 199 306 A1

Table 51

x

Y

; Z R 3H H

Example Y

R i R 2 R 3

or ring structure formed by X, Z, R,, R 2
and/or R 3 taken together

A r

R ' i

518 CO

519 CO

520 CO

521 CO

522 CO

523 CO

H

FT

R'

H

H same as the above same as the above J-J

H same as the above same as the above H

H same as the above same as the above H

H same as the above same as the above H

H same as the above same as the above H

524 CO

H same as the above same as the above H

525 CO

526 CO

527 CO

528 CO

H same as the above same as the above H

H same as the above same as the above H

H same as the above same as the above H

H same as the above same as the above H

123

EP 1 199 306 A1

Table 52

A Z-R 3H H

VyY*

k/ 1 o

Example Y R i ^2 R 3

or ring structure formed by X, Z, R,, R 2
and/or R 3 taken together

A r

R' i

529 CO

530 CO

531 CO

H

R'

H same as the above same as the above H

H same as the above same as the above H

532 CO

533 CO

534 CO

535 CO

N

O

H same as the above same as the above H

H same as the above same as the above H

M same as the above same as the above H

H same as the above same as the above H

536 CO

H same as the above same as the above H

537 CO

N

H same as the above same as the above H

538 CO

H same as the above same as the above H

539 CO

same as the above same as the above H

124

EP 1 199 306 A1

Table 53

x

Y

Z-R

3H

H
N

O

Example Y R i R 2 R 3

or ring structure formed by X, Z, R 1( R 2
and/or R 3 taken together

A r

R* i

R'

540 CO

541 CO

542 CO

543 CO

544 CO

545 CO

546 CO

547 CO

N

O

N

H

-1

H same as the above same as the above H

H same as the above same as the above H

H same as the above same as the above H

H same as the above same as the above H

H same as the above same as the above H

H same as the above same as the above H

H same as the above same as the above H

125

EP 1 199 306 A1

Table 54

X \ R3 H H

Y Ar

Example Y

R i R 2 R 3
or ring structure formed by X, Z, R, , R 2
and/or R 3 taken together

A r R ' i R '

R'

548 CO

549 CO

same as the above

H

R' 2

H

same as the above H

•N >

H

H

550 CO

same as the above

same as the above H

H

551 CO

same as the above

same as the above H

H
u

H

552 CO

same as the above

same as the above H

H

553 CO

same as the above

same as the above H

H

H

554 CO

same as the above

same as the above }~i

H

H

555 CO

same as the above

same as the above H

.(J

H

556 CO

557 CO

same as the above

same as the above

same as tha above H

same as the above H

V
Vx

H

H

558 CO

same as the above

same as the above H

H
N

H

126

EP 1 199 306 A1

Table 55

X— Z-R 3 H H

Example Y R i R 2 R 3

or ring structure formed by X, Z, R, , R 2
and/or R 3 taken together

559 CO

560 CO

561 CO

562 CO

563 CO

564 CO

565 CO

566 CO

567 CO

568 CO

569 CO

Ar R ' i R' 2 R ' 3

H

H

same as the above same as the above H

same as the above same as the above H

H

H

same as the above same as the above H

H

same as the above same as the above H

same as the above same as the above H

H

H

H

H

same as the above same as the above H

H

.N

H

same as the above same as the above

same as the above same as the above H

H

H

oh H

same as the above same as the above H

same as the above same as the above H

H r

OH H

H

127

EP 1 1 99 306 A1

Table 56

x

t

V

3H H

Example Y R i R 2 R 3

or ring structure formed by X, Z, R,, R 2
and/or R a taken together

Ar R* 1 R *

570 CO

571 CO

572 CO

573 CO

H

R"

H ^AfjH

same as the above same as the above H

same as the above same as the above H

same as the above same as the above H

VP

H r OH

H

R*

H

H

H

H

574 CO

575 CO

same as trie above same as the above H

H

same as the above same as the above H

H

XT

H

H

576 CO

same as the above same as the above H

H

H

577 CO

same as the above same as the above

H °*CU3 H

578 CO

579 CO

580 CO

same as the above same as the above

same as the above same as the above

H ^ XZ^-Q, H

same as the above same as the above H

H

H

128

EP 1 199 306 A1

Table 57

R .1 Ro

X Z-R 3H H
^ N Y N ^r

o

Example Y

R i R 2 R 3
or ring structure formed by X, Z, R„ Rj
and/or R 3 taken together

Ar R * j R*

R*

581 CO

582 CO

H

"YV,

H

same as the above same as the above H

H

H

583 CO

584 CO

585 CO

same as the above same as the above H

same as the above same as the above H

same as the above same as the above 1A

H

H

H

H

586 CO

587 CO

588 CO

589 CO

same as the above same as the above H

same as the above same as the above 3rl

same as the above same as the above H

same as the above same as the above H

H

H

H

H

H

590 CO

591 CO

same as the above same as the above H

same as the above same as the above H

H

H

H

H

129

EP 1 199 306 A1

Table 58

X Z-R 3H H

Y Ar
o

Example Y R i R 2 R 3

or ring structure formed by X» Z, R,, R 2
and/or R 3 taken together

Ar R' x R '

R'

592 CO

593 CO

594 CO

H

R':

same as the above same as the above

H

H

same as the above same as the above H

H

H

H

H "^C^c, H

595 CO

same as the above same as the above H

H

.N

CI

H

596 CO

597 CO

same as the above same as the above H

same as the above same as the above H

CI

H

H

598 CO

599 CO

600 CO

601 CO

602 CO

same as the above same as the above M e

same as the above same as the above

same as the above same as the above

same as the above same as the above

same as the above same as the above H

„ ^

H

h h

H

H

H

130

EP 1 199 306 A1

Table 59

X Z-R 3H H

T Ar

o

Example Y Ri ^2 R 3 Ar R ' i

or ring structure formed by X, Z, R,, R 2

and/or R 3 taken together

603 CO

604 CO

605 CO

H

H

same as the above same as the above H

same as the above same as the above H

R *

R "

H

H

H

606 CO

same as the above same as the above H

H

607 CO

same as the above same as the above H

H

608 CO

609 CO

610 CO

611 CO

same as the above same as the above H

same as the above same as the above H

same as the above same as the above H

same as the above same as the above H

H

H

-N

ft

^5

H

H

H

H

612 CO

same as the above same as the above H

H

613 CO

same as the above same as the above

H «>0

H

131

EP 1 199 306 A1

Table 60

X Z R 3H H

Example Y R i R 2 R 3

or ring structure formed by X, Z, R), R 2
and/or R 3 taken together

A r R' 1 R'

R '

614 CO

615 CO

616 CO

617 CO

618 CO

619 CO

620 CO

621 CO

622 CO

623 CO

H

H

same as the above same as the above H

same as the above same as the above H

same as the above same as the above H

same as the above same as the above H

same as the above same as the above H

same as the above same as the above H

same as the above same as the above H

same as the above same as the above H

same as the above same as the above H

'<5

H

H

H

H

H

H

H

H

H

H

H

H

624 CO

same as the above same as the above H

H

132

EP 1 1 99 306 A1

Table 61

R ,1 ,Ro

X ; X ?~R3H H

Example Y

R i R 2 R 3
or ring structure formed by X. Z, R ( , R 2
and/or H 3 taken together

Ar R ' ! R'

625 CO

626 CO

627 CO

H

V N

R':

3 V.

H

same as the above same as the above H

same as the above same as the above H

X

R'

H

H

628 CO

629 CO

630 CO

631 CO

632 CO

633 CO

634 CO

same as the above same as the above H

same as the above same as the above H

same as the above same as the above H

same as the above same as the above H

same as the above same as the above H

same as the above same as the above H

same as the above same as the above H

X

X

H

H

H

H

H

H

H

H

635 CO

same as the above same as the above

H

h v-q

H

133

EP 1 199 306 A1

Table 62

A Z R 3H |_|

Y Ar
o

Example Y R 1 R 2 R 3

or ring structure formed by X, Z, R,, R 2
and/or R 3 taken together

Ar R* 1 R*

636 CO

637 CO

H

" sr Vr i

same as the above same as the above

H ^

R'

H

H

638 CO

639 CO

same as the above same as trie above H

same as the above same as the above H

,OH

H

H

640 CO

same as the above same as the above H

H
N

H

641 CO

same as the above same as the above H

H

H

642 CO

same as the above same as the above H

H

643 CO

same as the above same as the above

H

H

H

644 CO

same as the above same as the above H

H
N

H

645 CO

same as the above same as the above H

H

■N

H

646 CO

same as the above same as the above H

H

134

EP 1 1 99 306 A1

Table 63

X Z R 3H H

o

Example Y R L R 2 R 3 A. r R'x

or ring structure formed by X, Z, R,, R 2

and/or R 3 taken together

R'

647 CO

648 CO

649 CO

650 CO

H

Me

same as the above same as the above M e

same as the above same as the above M e

same as the above same as the above M e

H

R'

H

X> H

H

H

H

651 CO

same as the above same as the above M C

H

652 CO

same as the above same as the above M €

H

653 CO

654 CO

655 CO

same as the above same as the above M C

same as the above same as the above M e

same as the above same as the above M C

H

H

H

V H

H

656 CO

same as the above same as the above M 6

H

-N

H

657 CO

same as the above same as the above H

H

H

135

EP 1 1 99 306 A1

Table 64

R .1 Ro

X Z-R 3H H

Y Ar
o

Example Y

R i R 2 R 3
or ring structure formed by X, Z, R,, R 2
and/or R 3 taken together

Ar R ' i R'

658 CO

659 CO

H

3 V

H

same as the above same as the above H

R *

H

H

660 CO

same as the above same as the above H

H

H

661 CO

same as the above same as the above H

H

H

662 CO

same as the above same as the above H

H
N

H

663 CO

same as the above same as the above H

H

664 CO

same as the above same as the above H

O H

665 CO

same as the above same as the above H

o »

666 CO

same as the above same as the above H

H

H

667 CO

same as the above same as the above H

H

H

668 CO

same as the above same as the above H

H
N

H

136

EP 1 199 306 A1

Table 65

R«1 ,Ro
X Z-R 3H H

Example Y

R i R 2 R3
or ring structure formed by X, Z, R,, R 2
and/or R 3 taken together

Ar R ' ! R '

669 CO

670 CO

H

H

same as the above same as the above H

H
N

H

H

H

671 CO

same as the above same as the above H

H

HE

672 CO

same as the above same as the above H

H

H

673 CO

same as the above same as the above

H

674 CO

same as the above same as the above H

H

H

675 CO

same as the above same as the above H

H
N

H

676 CO

677 CO

678 CO

679 CO

same as the above same as the above

same as the above same as the above

same as the above same as the above

H

H

same as the above same as the above H

H

H

H ^JlXX H

H H
1

137

EP 1 1 99 306 A1

Table 66

R ,1 Ro

X— Z-R 3 H H

YY Y Ar

o

Example Y Ri Rz ^3 Ar

or ring structure formed by X, 2, R,, R 2
and/or R 3 taken together

R ' x R*

680 CO

681 CO

H

same as the above

H

same as the above H

R '

H

■ji5b h

682 CO

same as the above

same as the above H

H
N

H

683 CO

same as the above

same as the above

„ H

684 CO

same as the above

same as the above H

H

685 CO

686 CO

same as the above

same as the above

same as the above H *^^Y^X^^^ H

NH

h

same as the above H ^✓N^v^v^ j-j

687 CO

same as the above

same as the above H

H
N

H

688 CO

689 CO

690 CO

H same as the above H

H same as the above H

N

us

o

H same as the above

H

H

H

H

H

138

EP 1 199 306 A1

Table 67

R ,1 ,Ro

v; X ~"\ 3 H H

Y Ar

o

Example Y Ri R2 R3 Ar R'i

or ring structure formed by X, Z, R,. R 2

and/or R 3 taken together

R'

R'

691 CO

692 CO

H

R'

3 \

same as the above same as the above

H -Q^h

-^NHz H

693 CO

694 CO

695 CO

same as the above same as the above

same as the above same as the above

same as the above same as the above

" OH

H -y^J^nO H

696 CO

697 CO

698 CO

699 CO

700 CO

same as the above same as the above

same as the above same as the above

same as the above same as the above

same as the above same as the above

same as the above same as the above

H ^fp^) H

h "^rV^ 1 h

H W^N^^ H

139

EP 1 1 99 306 A1

Table 68

Rl JR

X— 2-R 3H H

Example Y R i

R

R

A r

R' ! R '

or ring structure formed by X, Z, H u R 2
and/or R 3 taken together

701 CO

702 CO

H

H

same as the above same as the above pi

H

R '

H

H V

703 CO

704 CO

same as ihe above same as the above

same as the above same as the above

H

H

H

OH

705 CO

same as the above same as the above M 6

H

H

140

EP 1 1 99 306 A1

Table 69

"1 ,R,
X-2-R 3H H

Example

Y

R i R z ^ 3
or ring structure formed by X, Z, R 1p R 2
and/or R 3 taken together

^4

A r

R* 1

706

CO

D "

C i

H

H

H

707

CO

same as the above

B r

H

same as the above

H

H

708

CO

same as the above

B r

B r

same as the above

H

709

CO

same as the above

C 1

C I

same as the above

H

H

141

EP 1 199 306 A1

Table 70

X»Z-R 3 H H

Example

X-R i R 2 R3

or ring structure formed by X, Z, R 1f R 2
and/or R 3 taken together

A r

R * ! R*

710 S0 2

-<

N

C O

H

H

711 SO

N =

same as tne above H

H

712 SO

713 SO

N

N =

C O

same as the above

same as the above

H

H

H

H

714 SO

NH

H

H same as the above H

H

715 S O 2

N

H

H same as the above H

H

Note 1 : N = means that a double bond is formed by nitrogen atom together with Z.

Accordingly the compound of Example 71 1 is shown by the formula:

0*7

Note 2: The thick letter N means that the nitrogen atom forms a chemical bond with each of Y and Z .

Accordingly the compound of Example 710 is shown by the formula:

Working Example No.1

[0366] To 4-amino-9-fluorenone (29 mg, 0.15 mmol) a solution of 2-pyridinecarbonylazide (22 mg, 0.15 mmol) in tet-
rahydrofuran (0.5 ml) was added at room temperature. The reaction mixture was refluxed for 2 hours and then cooled to
room temperature. To the reaction mixture, a mixture of hexane and ethyl acetate was added for crystal izati on. The re-
sulting crude product was washed with ethyl acetate and methanol successively and the crude product was filtrated to

142

EP 1 199 306 A1

afford the titled compound (the compound of working example No.1) (34 mg) as yellow powder.

1 H-NMR(DMSO-d 6 )8:7.07(1H,J=8.3Hz,5.1Hz),7.34-7.45(4H,m), 7.64-7.69(2H,m),7.78-7.84(1 H,m),8.04(1 H,d,J=7.9Hz),

8.08 (1 H,d,J=7.7Hz),8.29(1H,dd,J=5.0Hz,1 .2Hz),10.0(1 H,s), 11 .1 (1 H,brs).

mass:316(M+1)+.

5

Working Examples No.2 to 8

[0367] According to the procedure described in the working example No.1 , the compounds of working examples
from No.2 to No. 8 were prepared.

10

Working Example No.2

[0368] 1 H-NMR(DMSO-d 6 )5:2.35(3H,s), 7. 02-7. 11(11-1171), 7. 34-7.48 (3H,m),7.60-7.74(3H,m),8.02-8.22(3H,m),8.1 9
(1H,m),8.92 (1H,m),12.1(1H,m).
15 mass:330(M+1)+.

Working Example No.3

[0369] 1 H-NMR(DMSO-d 6 ) 8:7.01 (1 H,dd,J=5.6Hz, 8.0Hz), 7.26 (1 H,dd,J=2.0Hz, 8.0Hz), 7. 35-7.46 (3H,m),7.67 (2H,
20 d,J=7.3 Hz), 7. 81 (1 H,dd,J=2.0Hz,5.6Hz),8.1 1 (1 H,dd,J=1 .8Hz,7.3Hz), 8.1 5(1 H ,d, J=7.3Hz),8. 40(1 H,s),1 1 .8(1 H,s).
mass:332(M+1)+.

Working Example No.4

25 [0370] 1 H-NMR(DMSO-d 6 )5:3.28(2H,s),7.36-7.46(6H,m),7.56(3H,d,J= 7.6Hz), 7. 62-7. 70(2H,m), 7.69(1 H ; dd,J=5.0Hz,
8.0Hz), 7.88 (1 H,d,J=5.0Hz), 8.04-8. 14(2H,m), 8.48(1 H,s),11 .8(1 H,s).
mass:422(M+1) + .

Working Example No.5

30

[0371] 1 H-NMR(DMSO-d 6 )8:7. 23-7.28(1 H,m), 7.39-7. 48(3H,m),7. 65-7. 70(2H 5 m),8. 07-8. 10(2H 3 m) 3 8.48(1 H,dt, J=

7.8Hz, 1.6Hz), 8.56(1 H,d, J=5.0Hz).

mass:360(M+1)+.

35 Working Example No.6

[0372] 1 H-NMR(DMSO-d 6 )S:2.35(3H,s), 6.96(1 H,d,J=5.0Hz), 7.15(1 H,s), 7.36-7.49(3H,m), 7.64-7.74(2H,m),

8.08-8.1 5(2H,m), 8.19 (1H,d,J=5.0Hz),1 0.0(1 H,s),11 .3(1 H.brs).

mass:330(M+1)+.

40

Working Example No.7

[0373] 1 H-NMR(DMSO-d 6 )5:7.18(1H,d,J=6.0Hz),7.35-7.45(3H,m), 7.57(1 H,s), 7. 62-7.67(2H,m),7. 93(1 H,d,J=7.0Hz),
7.98 (1 H,d,J=7.0Hz) ! 8.28(1 H,d,J=4.0Hz),1 0.1 (1 H,s),1 0.4(1 H,s).

45

Working Example No.8

[0374] 1 H-NMR(DMSO-d 6 )5:2.97(6H ! s),6.43(1H,s),6.43(1H : dd ) J=7.3Hz, 2. 0Hz), 7.33-7.41 (3H,m), 7. 62-7. 67(2H,m),
7.88(1 H,d,J=6.0 Hz) ) 8.14(1H,d ) J=6.7Hz) l 8.20(1H,d,J=6.7Hz),9.63(1H,s).

50

Working Example No.9

[0375] According to the procedure described in the working example No. 26, the compound of reference example
No.1 and 2-amino-4-(N-ethoxycarbonyl)amonopyridine were used to afford the intermediate(50 mg, 0.12 mmol), which
55 was dissloved in the ethanol (2 ml). 5N aqueous sodium hydroxide (2.0 ml, 1 0 mmol) was added at room tmperature.
The whole was refluxed for 1 hour. The reaction mixture was cooled to room temperature and water was added. The
whole was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine and dried
over magnesium sulfate. After filtration, the filtrate was concentrated to afford a residue, which was purified by column

143

EP 1 199 306 A1

chromatography on silica gel. The fraction eluted with chloroform-methanol (1 00:0-95:5) provided the titled compound
(8 mg) as yellow crystals.

1 H-NMR(DMSO-d 6 )5:6.19(1H,s),6.25(1H,d,J=5.9Hz),6.28 (2H,s), 7.34-7. 41 (3H,m),7.62-7.69(2H,m),7.74(1 H ; d,J=5.7
Hz), 8. 1 5(1 H,d,J=7.1Hz),8. 21 (1 H,d : J=7.1 Hz),9. 66(1 H ; s), 12.3(1 H,br).
5 mass:331 (M+1)+.

Working Example No.1 0

[0376] The compound (33 mg. 0.10 mmol) of working example No. 9 was dissloved in tetrahydrofuran (3 ml). N-
10 butylaldehyde (27 jal, 0.30 mmol) and sodium triacetoxyborohydride (63 mg, 0.30 mmol) were added at room temper-
ature. The mixture was stirred for 6 hours at the same temperature. To the reaction mixture , saturated aqueous sodium
hydogencarbonate was added. The whole was extrated with ethyl acetate-tetrahydrofuran. The organic layer was
washed with saturated brine and dried over magnesium sulfate. After filtration, the filtrate was concentrated to afford
a residue, which was purified by TLC. The fraction eluted with chloroform -tetrahydrofuran (70:30) provided the titled
*s compound (23 mg) as yellow crystals.

1 H-NMR(DMSO-d 6 )6:0.90(3H,t,J=7.2Hz),1. 31 -1.40(2H,m), 1.48-1 .53(2H,m),2.98-3.02(2H,m),6.1 9(1 H,s),6.28(1 H,d,
J=6.1Hz, 1.9Hz),6.79(1H,dt),7.31-7.40(3H,m),7.62-7.68(2H ; m),7.75 (1 H,dJ=6.2Hz),8. 1 4(1 H,dd, J=7.1 Hz,1 .9Hz),8.20
(1H,d,J=8.2Hz) ,9.60(1 H,s), 12.3(1 H,br).
mass:387(M+1)+

20

Working Example No.11

[0377] According to the procedure described in working example No. 80(3), 4-amino-9-flurorene which replaces the
compound of reference example No. 3 and the compound of working example No. 80(2) were used to afford the crude
25 compound. According to the procedure described in working example No. 80(4), the crude compound was used to afford
the titled compound (21 mg) as colorless crystals.

1 H-NMR( CDCI 3 )5:4.52(2H,d,J=5.3Hz),5.47(1H,t,J=5.3Hz),7.00(1H, d,J=4.7Hz) ; 7.28-7.69(6H,m), 8.05-8.22(3H,m),
10. 0(11-1, s), 11.4(1H,s).
mass:346 (M+1)+.

30

Working Examples No.12 to 17

[0378] According to the procedure described in the working example No.1 , the compounds of working examples
from No.12 to No.1 7 were prepared.

35

Working Example No.12

[0379] 1 H-NMR(DMSO-d 6 )5:2.28(3H,s), 7.25(1 H,d,J=7.6Hz), 7.16-7.45 (3H,m), 7.63-7.72(3H,m), 8.04-8.1 4(3H,m),
9. 92(11-1, s), 11.1 (1H,br).
40 mass:330(M+1)+.

Working Example No.1 3

[0380] 1 H-NMR(DMSO-d 6 )5:7.34-7.47(3H,m),7.58(1H,d,J=8.9Hz),7.66 (2H,m),7.95(1 H,d,J=7.8Hz),7.99(2H,m),
45 8.31(1H,d,J=2.6Hz),10. 0(1H,br).
mass:350 : 352(M+1)+.

Working Example No.1 4

50 [0381] 1 H-NMR(DMSO-d 6 )5:7. 35-7.48(3H,m), 7.54(1 H,d,J=8.9Hz), 7. 62-7. 72(2H,m), 7. 93(1 H,d,J=9.2Hz),7.96(1 H,d,
J=5.1 Hz), 8.00(1 H,dd ,J=8.9Hz,2.2Hz), 8.39(1 H,d,J=2. 8Hz), 10.1(1H,m).
mass:394 ; 396(M+1)+.

Working Example No.1 5

55

[0382] 1 H-NMR(DMSO-d 6 )5:7.36-7.56(4H,m), 7.64-7.74(2H,m), 7.96 (2H,t,J=8.6Hz), 7.94-8.02(1 H,m),8.60(1 H,m),

9.16(1H,m).

mass:361(M+1)+.

144

EP 1 199 306 A1

Working Example No.1 6

[0383] 1 H-NMR(DMSO-d 6 )5:7.39-7.49(6H,m), 7.68-7. 73(3H,m),7. 99-8. 08(3H,m),8. 23-8. 26(1 H,m),8.80(1 H,s).
mass:359(M+1)+.

5

Working Example No.1 7

[0384] 1 H-NMR(DMSO-d 6 )5:7. 37-7.48(3H,m), 7.55(1 H,d,J=8.8Hz),7. 62-7. 69(2H,m),7. 95(1 H,d,J=7.9Hz),8.02(1 H,d,
J=6. 9Hz), 8.25(1 H,dd ,J=8.8Hz,2.3Hz),8.79(1 H ,d,J=2.2Hz).
10 mass:360(M+1)+.

Working Example No.1 8

[0385]

15

(1) According to the procedure described in the working example No. 26, the compound of reference example No.
1 and 2-amino-5-(N-tert-butoxycarbonyl) aminopyridine were used to afford an intermediate (0.61 3 g, 1 .40 mmol),
to which was added trifluoroacetic acid (10 ml) at room temperature. The mixture was stirred for 6 hours at the
same temperature. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate.

20 The whole was extrated with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine

and dried over magnesium sulfate. After filtration, the filtrate was concentrated to afford a residue, which was
purified by column chromatography on silica gel. The fraction eluted with chloroform-methanol (1 00:0-90:1 0) pro-
vided crude crystals. According to the procedure described in working example No. 80(3), a crude crystal (0.431
g), which was further washed with ether to afford the compound as yellow crystals (0.302 g).

25 (2) According to the procedure described in the working example No.1 0, the titled compound (3.4 mg) as a yellow

crystal was prepared from the compound (33 mg) obtained above in (1).

1 H-NMR(DMSO-d 6 )5:0.93(3H,t,J=7.2Hz),1 .37-1 .43(2H,m),1 .50-1 .57(2H,m),2. 97-3. 03(2H,m),5. 59(1 H,t),

7.11-7.13(2H ) m) ) 7.35-7.45(3H ) m) ) 7.64-7.70(3H ) m),8.11-8.16(2H ) m),9.61(1H,s).

mass:387(M+1)+.

30

Working Examples No.1 9 to 20

[0386] According to the procedure described in the working example No. 26, the compounds of working examples
from No.1 9 to No. 20 were prepared.

35

Working Example No.1 9

[0387] 1 H-NMR(DMSO-d 6 )5:3.81(3H,s),7.05(2H,d,J=8.8Hz),7.38-7.47 (4H,m),7.64-7.70(4H,m),8.02-8.1 3(3H,m),
8.54(1 H,d,J=2.6Hz), 1 0.1 (0.3H,s),1 1 .0(0.2H,br).
40 mass:422(M+1)+.

Working Example No.20

[0388] 1 H-NMR(DMSO-d 6 )5:2.51(3H,s),7.04(1H,d,J=7.1 Hz), 7.21 -7.27 (1 H,m), 7.47-7. 59(3H,m), 7. 72-7. 84(3H,m),
45 8.00-8.04(1 H,m), 8.1 7(1 H,d,J=7.6Hz),1 0.1 (1 H,s),11 .3(1 H,brs).
mass:330(M+1)+

Working Example No.21

so [0389] According to the procedure described in the working example No.1 8 (1), the compound of reference example
No.1 and 2-amino-6-(N-tert-butoxycarbony)aminopyridine was used to afford the titled compound.
1 H-NMR(DMSO-d 6 )S:6. 07-6,1 0(2H,m), 6. 28(1 H ; d,J=7.5Hz), 7. 34-7.41 (4H,m), 7.46-7.48(1 H,m), 7. 52-7. 57(1 H,m), 7. 65
(1 H,d,J= 6. 7Hz), 7.77(1 H,d,J=7.1 Hz),7. 93(1 H, d,J=7.6Hz), 9.55(1 H,s), 1 1 .6(1 H,brs).
mass:331 (M+1)+.

55

Working Example No.22

[0390] According to the procedure described in the working example No.1 0, the compound of working example No.

145

EP 1 199 306 A1

21 was prepared.

1 H-NMR(DMSO-d 6 )S:0.68(3H,t,J=7.4Hz), 1 .03-1 .1 5(2H,m), 1 .32-1 .42(2H,m), 2.99-3. 05(2H,m), 6.07(1 Kd^S^Hz),
6.31 (1H,d, J=7.8Hz), 6.65(1 H,t,J=5.4Hz), 7.34-7. 40(3H,m), 7.48(1 H,d,J= 6.3Hz), 7.55(1H,dd,J=7.6Hz, 6.4Hz), 7.65
(1H,d,J=7.3Hz), 7.70(1H , d,J=7.2Hz), 7.81 (1 H,d,J=7.4Hz), 9.56(1 H,s), 1 1 .4(1 H,br).
5 mass : 387 (M+1) + .

Working Examples No.23 to 25

[0391] According to the procedure described in the working example No. 26, the compounds of working examples
10 from No.23 to No. 25 were prepared.

Working Example No.23

[0392] 1 H-NMR(DMSO-d 6 )S:1 .1 6(3H,t,J=7.4Hz),2.36(3H,s),2.73(2H,q, J=7.6Hz),6.94(1 H,d,J=7.7Hz) ; 7.36-7.47(3H,
15 m), 7. 57-7.68 (3H,m),7.88(1 H,d,J=7.9Hz),8.06(1 H,d,J=7.0Hz).
mass:358(M-i-1) + .

Working Example No.24

20 [0393] 1 H-NMR(DMSO-d 6 )8:2.26(3H ! s),2.34(3H,s) ) 6.77(1H : s),6.89 (1 H,s),7.38-7.43(3H,m) ) 7.63-7.68(2H ) m),7.90
(1 H,dd,J=8.0Hz, 1 .9Hz),8.05(1 H,d,J=7.5Hz),9.92(1 H,s),1 1 .4-11 .5 (1 H.br).
mass:344(M-i-1). +

Working Example No.25

25

[0394] 1 H-NMR(DMSO-d 6 )5:2.39(3H ! s) ) 2.41(3H ) s),6.94(1H : s) ) 7.37-7.48(3H ! m) ) 7.60-7.69(2H ) m) ) 7.88(1H ) d )

J=7.9Hz),8.04(1H,d, J=7.6Hz),8.1 1 (2H ( brs),8.77(0.7H,s),9.02(0.3H,s).

mass:387(M+1) + .

30 Working Example No.26

[0395] To a solution of 2-aminopyridine (13 mg, 0.14 mmol) in tetrahydrofuran (1 ml) a solution of the compound
(1.25 mg, 0.1 mmol) in tetrahydrofuran (1 ml), was added. The mixture was refluxed for 30 minutes. The crystals
precipitated were collected by filtration. The crude product was washed with chloroform and then dried to afford the
35 titled compound (1 0 mg) as yellow crystals.

1 H-NMR(DMSO-d 6 )6:7. 23(1 H,t ) J=4.9Hz) 1 7.38-7.50(3H ) m),7. 67-7. 72(2H,m) J 8- 06-8. 1 0(2H,m),8.74(2H,d,J=4. 9Hz),

10.6(0.31-1, s) 5 11.6(0.3H,s).

mass:317(M+1) + .

40 Working Examples No.27 to 53

[0396] According to the procedure described in the working example No.26, the compounds of working examples
from No.27 to No. 53 were prepared.

45 Working Example No.27

[0397] 1 H-NMR(DMSO-d 6 )5:7.36-7.95(9H,m).
mass:333(M-i-1) + .

50 Working Example No.28

[0398] 1 H-NMR(DMSO-d 6 )d:3.28(3H,s),7.07(1 H,d,J=5.3Hz), 7.36-7. 97(6H,m), 8. 05(1 H,d,J=7.3Hz),8.53(1 H,d).
mass:331(M+1)+.

55 Working Example No.29

[0399] 1 H-NMR(DMSO-d 6 )8:2.38(3H,s),2.52(3H,s),7.27-7.35(3H,m), 7.53-7.57(2H,m),7.81 (1 H,d,J=7.9Hz),7.90(1 H,
d,J=7.6Hz), 9.00(1 H.s).

146

EP 1 199 306 A1

mass:373(M+1)+.
Working Example No.30

5 [0400] 1 H-NMR(DMSO-d 6 )8:2.27(3H ! s),2.38(3H,s) ) 7.36-7.48(3H,m) ) 7.65-7.70(2H,m),7.75-7.78(1 H,m),7.92(1 H,d,
J=7.4Hz), 9.02(1 H.brs).
mass:345(M+1)+

Working Example No.31

10

[0401] 1 H-NMR(DMSO-d 6 )8:3. 34(3H,s),3.92(3H,s), 7.39-7.51 (4H,m), 7.69-7.81 (3H,m), 7.99(1 H,d,J=7.6Hz).
mass:377(M+1)+.

Working Example No.32

15

[0402] 1 H-NMR(DMSO-d 6 )5:2.19(3H ! s) ) 5.95(1H ) br) ) 6.75(1H ) br) 5 7.39-7.44(2H 5 m) ) 7.49-7.52(1H ) m) ) 7.63-7.69(2H )
m), 7. 78-7.81 (1 H,m), 7. 94-7. 97(1 H,m).
mass:347 (M+1)+.

20 Working Example No.33

[0403] 1 H-NMR(DMSO-d 6 )8:1 .76,1 .89(3H,sx2), 2.01, 2.1 8(3H,sx2), 7.37-7.50(5H,m), 7.61 -7.67(2H,m), 7.77-7.80
(1H,m), 7.93-7.97(1 H,m).
mass : 361 (M+1)+.

25

Working Example No.34

[0404] 1 H-NMR(DMSO-d 6 )5:7.43-7.53(3H,m), 7.68-7.73(2H,m), 7.94-8. 02(2H,m), 8.34-8.39(2H,m), 8.99(1 H,s).
mass:317(M+1)+.

30

Working Example No.35

[0405] 1 H-NMR(DMSO-d 6 )5:6. 60(1 H,brs), 7.33-7. 49(7H,m), 7. 63-7.75 (4H,m),7.91 -8.05(2H,m).
mass:381 (M+1)+.

35

Working Example No.36

[0406] 1 H-NMR(DMSO-d 6 )5:5. 85(2H,brs), 7.30-7. 45(5H,m), 7. 61 -7.69 (2H,nri),8.1 3-8.20(1 H,m).
mass:321 (M+1)+.

40

Working Example No.37

[0407] 1 H-NMR(DMSO-d 6 )5:1 .34(3H,t,J=7.5Hz),4.05(2H,q,J=7.5Hz), 6.1 8(1 H,m), 7.33-7. 46(4H,m),7.63-7.73(3H,
m),7.84(1H,d, J=7.5Hz).
45 mass:333(M+1)+.

Working Example No.38

[0408] 1 H-NMR(DMSO-d 6 )8:6.45(1H,s),7.31-7.47(4H,m),7.54-7.63 (8H, m), 7.69(1 H,d,J=7.5Hz), 8. 79(1 H,s), 8. 95(1 H,
50 S ).

mass:381(M+1)+.

Working Example No.39

55 [0409] 1 H-NMR(DMSO-d 6 )8:1 .39(3H, s), 5. 45(1 H,s), 6.49-6. 61 (4H,m), 6.69-6.85(8H,m),7.91 (1 H,brs),8.06(1 H,brs).
mass:395(M+1)+.

147

EP 1 199 306 A1

Working Example No.40

[0410] 1 H-NMR(DMSO-d 6 )5:6. 33(1 H,dJ=3.8Hz), 6.55-6. 66(4H,rn), 6. 81 -6. 85(2H,m),7. 00-7.04(1 H,m),7.08(1 H,d :
J=7.6Hz),8.03(1H,brs).
5 mass : 322 (M+1)+.

Working Example No.41

[0411] mass:336(M+1)+.

10

Working Example No.42
[0412] mass: 422(M-M) + .
15 Working Example No.43

[0413] mass: 408(M+1)+.
Working Example No.44

20

[0414] 1 H-NMR(DMSO-d 6 )5:1.30(3H ! t,J=7.5Hz),4.31(2H,q,J=7.5Hz), 7.36-7.50(4H,rn),7.60-7.69(1 H,m),7.83(1 H,d,

J=7.5Hz), 7.90(1 H,d,J=7.5Hz),8.72(1 H,s).

mass:437(M+1)+.

25 Working Example No.45

[0415] 1 H-NMR(DMSO-d 6 )5:7. 29-7.50(6H,m), 7.55(1 H,s), 7. 60-7.66 (2H,m),7.81 -7.94(4H,m).
mass:398(M-i-1) + .

30 Working Example No.46

[0416] 1 H-NMR(DMSO-d 6 )S:7.40(2H ! t),7.49(3H,d),7.60-7.66(3H,m), 7.83(1 H ,d,J=7.6Hz), 7.91 (3H,d.J=7.6Hz).
mass : 432 (M+1)+.

35 Working Example No.47

[0417] 1 H-NMR(DMSO-d 6 )8:7. 35-7.43(2H,m), 7.48-7. 52(1 H,m), 7. 60-7. 66(2H,m),7-72(1 H,d,J=7.6Hz),7. 81 (1H,d :

J=7.6Hz), 8.20-8. 28(3H,m) ! 8.38-8.44(2H,m), 8. 89-9. 02(0. 2H,br).

mass:507(M+1)+.

40

Working Example No.48

[0418] 1 H-NMR(DMSO-d 6 )5:2.45(3H,s),6.51-6.70(3H,m) ) 6.79-6.97 (4H,m) ; 7.1 3-7.37(1 H,m),7.80(0.3H,s), 8.20(0. 3H,
s).

45 mass:336(M+1)+.

Working Example No.49

[0419] 1 H-NMR(DMSO-d 6 )8:7.36-7.43(2H,m),7.47(2H,d,J=7.5Hz),7.61-7.65(2H ) m) ) 7.77(1H,d,J=7.5Hz),7.84(1H,d )
50 J=7.5Hz).

mass:400 : 402(M+1)+.

Working Example No.50

55 [0420] 1 H-NMR(DMSO-d 6 )8:7.35-7.45(2H,rn), 7.52(1 H,d,J=6.9Hz), 7.60-7.67(2H,m), 7.77(1 H,d,J=8.0Hz), 7.85(1 H.
d,J=7.5Hz), 8.60(1 H,s).
mass:367(M+1) + .

148

EP 1 199 306 A1

Working Example No.51

[0421] 1 H-NMR(DMSO-d 6 )5:7.25(1H,t),7.40(3H,t)7.48(1H,d,J=7.6Hz),7.60-7.68(3H,m), 7.86-7. 93(3H ; m),9.15(0.5H,
br).

5 mass:372 (M+1)+.

Working Example No.52

[0422] lH-NMR(DMSO-d 6 )S:1.49(3H,s), 6.41 (1 H,d,J=7.5Hz), 6.57-6.90 (7H ,m), 7. 00-7. 05(1 H,brm),7.1 0-7. 1 5(1 H,
10 brm).

mass:386(M+1)+.

Working Example No.53

15 [0423] 1 H-NMR(DMSO-d 6 )8:6.45(1H,dt), 6.60(2H,t), 6.70(1 H,d,J=7.6Hz), 6.80-6.90(3H,m), 7.00-7.1 0(3H,m).
mass:390(M+1)+

Working Examples No.54 and 55

20 [0424] According to the procedure described in the working example No.1, the compounds of working examples of
No.54 and No. 55 were prepared.

Working Example No.54

25 [0425] 1 H-NMR(DMSO-d 6 )5:7.07-7.11 (1 H,m), 7. 34-7.38(1 H,m), 7.53 (1 H,s), 7. 78-7. 84(2H,m), 7.92-7. 95(1 H,m),8.07
(1 H,d,J=8.3Hz), 8.32(1 H,d,J=1 .8Hz),8.38(1 H,s).

Working Example No.55

30 [0426] 1 H-NMR(DMSO-d 6 )5:7.06(1H,dd,J=7.2Hz ! 5.1 Hz), 7. 20-7.23(1 H,m), 7.42(1 H,d,J=7.3Hz), 7.71 -7. 80(2H,m),
8.35(1 H,dd,J=5.0Hz, 1.9 Hz) ) 8.74(1H ) d ! J=8.5Hz) ) 12.0(0.4H ; s) ) 11 ^(O^H^rs),^^^^.

Working Example No.56

35 [0427] A mixture of compound (56 mg, 0.20 mmol) of working example No.55, triphenylphosphine (157 mg, 0.6
mmol) and methanol (1 9 mg ; 0.60 mmol) was dissolved in dimethylformamide (5 ml). To the mixture was added a 60
% solution (0.17 ml) of diethylazodicarboxylate (0.60 mmol) in toluene at room temperature. The mixture was stirred
for 30 minutes at the same temperature. The reaction mixture was diluted with ethyl acetate and washed with water.
The organic layer was separated. The crystals precipitated were collected by filtration to afford the titled compound

40 (41 mg).

1 H-NMR(DMSO-d 6 )5:3.03(3H,s),7.04-7.09(1H,m),7.19(1H 5 brd, J=7.9Hz), 7.45(1 H,dd,J=7.2Hz,0.8Hz),7.70-7.81 (2H,
m),8.39 (1H,dd,J=5.0Hz,1 .9Hz),8.74(1 H,d,J=8.6Hz),1 0.2(0.3H,s),1 2.7 (0.3H,br).

Working Examples No.57 to 74

45

[0428] According to the procedure described in the working example No.56, the compounds of working examples
from No.57 to No. 74 were prepared.

Working Example No.57

50

[0429] 1 H-NMR(DMSO-d 6 )8:1.18(3H,t,J=7.2Hz) ! 3.60(2H ! q,J=7.2Hz), 7.07(1 H,dd,J=7.3Hz,5.0Hz), 7.1 9-7.21 (1 H,m),
7.42(1 H,d ; J=7.2Hz) ; 7.71 -7.81 (2H,m), 8.39(1 H,m),8.75(1 H,d,J=8.6Hz), 1 0.2(0.3H,s),12.7(0.3H,br).

Working Example No.58

55

[0430] 1 H-NMR(DMSO-d 6 )5:0.87(3H,t,J=7.4^

7.22(1 H, m), 7.46(1 H ,d,J=7.3Hz), 7.71 -7.81 (2H,m), 8.38(1 H ; m), 8. 75(1 H,d,J=8.5 Hz),1 0.2(0.3H,s),1 2.6(0.3H,br).

149

EP 1 199 306 A1

Working Example No.59

[0431] 1 H-NMR(DMSO-d 6 )5:1 .42(6H,d J=6.9Hz), 4.37-4.42(1 H,m),7. 05-7. 09(1 H,m),7. 21 -7.23(1 H,brm), 7.43(1 H,d,
J=7.2Hz),7. 70-7.81 (2H,m) ; 8.39(1 H,m),8.74(1 H,d ; J=8.5Hz),1 0.2(0.2H,s),1 2.6( 0.2H,br).

Working Example No.60

[0432] 1 H-NMR(DMSO-d 6 )5:0.90(3H ! t,J=7.3Hz),1.26-1.36(2H,m),1 .54-1 .63(2H,m),3.57(2H,t,J=7.0Hz),7.07(1 H,
ddd ; J=7.3Hz,5.0Hz,1 .0 Hz), 7.20(1 H,d,J=7.9Hz),7. 46(1 H,d,J=7.2Hz), 7. 71 -7.81 (2H,m),8.38(1 H,dd,J=5.0Hz,1 8Hz),
8.75(1 H,d,J=8.5Hz), 10.2 (1 H,s),1 2.6(1 H,br).

Working Example No.61

[0433] 1 H-NMR(DMSO-d 6 )8:1 .40-1 .47(2H,m),1 .61 -1 .68(2H,m),3.39(2H,t, J=6.4Hz),3.58(2H,t,J=6.8Hz),4.38(0.3H,
m), 7. 04-7.09(1 H,m), 7.1 9-7.22(1 H,m), 7.41 -7.47(1 H,m), 7.71 -7. 82(2H,m), 8. 34-8. 39 (1 H,m),8. 75(1 H,d,J=8.2Hz),1 0.2
(0.5H,s),12.6(0.4H,br).

Working Example No.62

[0434] 1 H-NMR(DMSO-d 6 )5:3.34-3.48(3H ) m) ) 3.59(2H,d,J=7.5Hz),4.43 (2H,m), 7. 05-7.09(1 H,m), 7.20(1 H,d,J=8.2Hz),
7.46(1 H,d, J=6.9Hz),7.71-7.81(2H ) m) ! 8.38(1H,dd,J=4.8Hz 5 1.6Hz),8.74 (1 H,d,J=8.6Hz),1 0.2(1 H,s), 12.6(1 H,br).

Working Example No. 63

[0435] 1 H-NMR(DMSO-d 6 )5:1 .21 (3H,t,J=7.1 Hz),4.1 6(2H,q,J=7.1 Hz), 4.42(2H,s),7.07(1 H,dd,J=7.2Hz,5.1 Hz), 7.1 8-
7.21 (1H,m), 7.54(1 H, d,J=7.3Hz), 7-75-7. 83(2H,m), 8.35-8. 38(1 H,m), 8. 81 (1 H,d,J=8.6Hz),1 0.2(0. 5H,s), 12. 7(0. 4H,br).

Working Example No.64

[0436] 1 H-NMR(DMSO-d 6 )8:4.78(2H,s), 7. 06(1 H,ddd,J=7.3Hz, 5.0Hz, 1 .0Hz),7.1 9-7.36(6H,m),7.50(1 H ; d,J=7.1 Hz),
7.74-7.80(2H,m), 8.36(1 H,dd,J=4.9Hz,1 .9Hz), 8.77(1 H,d,J=8.6Hz),1 0,2(0. 3H,s), 1 2.6(0. 3H,br).

Working Example No.65

[0437] 1 H-NMR(DMSO-d 6 )5:2.94(2H,t,J=7.3Hz),3.81(2H,t,J=7.3Hz), 7.08(1 H,dd, J=7.2Hz,5. 0Hz), 7.1 5-7. 33(6H,m),
7.43(1 H,d, J=7.3Hz),7.70-7.81(2H,m),8.37(1H,dd,J=4.8Hz,1 .4Hz),8.73 (1 H,d,J=8.6Hz),10.2(0.3H,s),12.6(0.3H,br).

Working Example No.66

[0438] 1 H-NMR(DMSO-d 6 )8:4.61 (2H,s),6.50(1 H,t,J=7.2Hz),6.67(1 H,d, J=7.7Hz),6.93-7.09(4H,m),7.1 7-7.22(1 H,
m), 7. 41-7.71 (2H,m), 7.74-7.80(2H,m), 8.36(1 H,d,J=4.7Hz), 8.78(1 H,d,J=8.6Hz), 1 0.2(0.5H,s), 1 2.6(0.5H,br).

Working Example No.67

[0439] 1 H-NMR(DMSO-d 6 )8:4.62(2H ! s), 6.41 -6.46(3H ; m), 6.95(1 H,t, J=7.9Hz), 7.06(1 H,dd,J=7.2Hz, 5.0Hz),
7.1 9-7.22(1 H,m), 7.50 (1 H,d,J=7.2Hz), 7.74-7.80(2H,m), 8.37(1 H,d,J=5.6Hz), 8.77 (1 H ; d,J=8.4Hz), 1 0.2(0.3H,s), 12.6
(0.3H,br).

Working Example No.68

[0440] 1 H-NMR(DMSO-d 6 )8:4.91(2H,s), 7.03(1 H,dt,J=6.3Hz, 1.1 Hz), 7.17 -7.29(2H,m), 7.42(1 H,dd,J=7.9Hz,
1.0Hz), 7.52(1 H,d, J=7.2Hz), 7.73-7.82(3H,m),8.31 (1 H,dd,J=4.5Hz,1 .5Hz), 8.44(1 H,dd, J=4.5Hz,1 .8Hz),8.79(1 H,d,
J=8.6Hz),10.2(0.3H,s),12.6(0.2H,br ).

Working Example No.69

[0441] 1 H-NMR(DMSO-d 6 )S:4.81(2H,s),7.06(1H,dd,J=7.2Hz,5.0Hz), 7.09-7.22(1 H,m),7.35(1 H,dd,J=7.8Hz,4.8Hz),
7.49(1 H,d, J=6.9Hz),7.72-7.80(3H,m),8.37(1 H,d,J=3.9Hz),8.48(1 H,dd, J=4.8Hz,1 .6Hz),8.60(1 H,s),8.76(1 H,d,

150

EP 1 199 306 A1

J=8.0Hz),10.2(0.3H,s),1 2.6(0.3H,br).
Working Example No.70

5 [0442] 1 H-NMR(DMSO-d 6 )8:4.81 (2H,s),7.04(1 H,dd,J=6.9Hz,5,5Hz), 7.1 8-7.21 (1 H : m),7.33(2H,d,J=5.7Hz), 7.51
(1H ! d ) J=7.2Hz) ! 7. 74-7.81 (2H ! m) ; 8.33(1H ! d ! J=3.9Hz) ! 8.51(2H ! d ! J=6.0Hz) ! 8. 78(1 H,d, J=8.6Hz),1 0.2(0. 4H,s),1 2.6
(0.3H,br).

Working Example No.71

10

[0443] 1 H-NMR(DMSO-d 6 )S:3.82(3H,s)A^

7.51 (1H,d, J=7.3Hz), 7.74-7. 80(2H,m),7.92(2H,d, J=8.5Hz), 8.34(1 H,d, J=4.0Hz),8.78(1 H,d,J=8.6Hz),10.2(0.2H,s),12.6
(0.2H,br).

15 Working Example No.72

[0444] 1 H-NMR(DMSO-d 6 )8:1 .65-1 .68(1 H,brm),1 .82-1 . 98(2H,brm), 2. 04-2. 1 4(3H,brm),4. 72-4. 76(1 H,brm),5.61 (1 H,
dd,J=10Hz, 1.2Hz), 5.82-5.86(1H ) m),7.03-7.06(1H,brm),7.21-7.27(1H ) brm) ) 7.42-7.45(1H ) rri),7.70-7.80(2H,m),8.36
(1H,brs),8.72-8.74(1H,m), 1 0.2(0. 4H,brs), 12.4(0. 4H,br).

20

Working Example No.73

[0445] 1 H-NMR(DMSO-d 6 )5:0.93-1.11 (2H,brm),1 .1 3-1 .1 6(3H,brm),1 .63-1 .74(6H,brm),3.42(2H,d,J=6.9Hz),7.08
(1 H,dt,J=6.2Hz,1 .1 Hz), 7 .19-7.23(1 H,brm),7.47(1 H,d,J=7.1 Hz),7.72-7.82(2H,m),8.38 (1 H,d,J=4.9Hz),8.75(1 H,d,
25 j=8. 6Hz), 10.2(0. 5H,s),12.7(0.4H,br ).

Working Example No.74

[0446] 1 H-NMR(DMSO-d 6 )8:2.28(4H ! m),2.49(4H,m),4.49(3H,s),5. 76-5. 85(1 H,m), 7. 04-7. 09(1 H,m),7.1 7-7.21 (1H,
30 brm),7.48(1H.d, J=7.2Hz), 7. 71 -7.80(2H,m), 8.35(1 H,d,J=4.2Hz) ! 8. 76(1 H,d, J=8.6Hz),1 0.2(0. 5H,s),1 2.6(0.5H,br).

Working Example No.79

[0447] According to the procedure described in the working example No.1 . the compound of the reference example
35 No. 3 and 2-pyridine carbonylazide was used to afford the titled compound.

1 H-NMR(DMSO-d 6 )6:1. 06-1. 20(1 H,m),2. 30-2. 43(2H,brm),2. 52-2. 57(1 H,m),3. 28-3.35(1 H,m),3. 50-3. 60(1 H,m),4.83
(1H,dd, J=10Hz,5.7Hz),7.06(1 H ) dd,J=7.2Hz ) 5. 1 Hz),7.28-7.33(2H J m) ) 7.46(1 H,t,J=7.7Hz),7. 76-7.82(1 H,m) ; 8.29-8.32
(2H,m),9.95 (1 H,s),11 .2(1 H,br).
mass:309(M-i-1) + .

40

Working Example No.80
[0448]

^5 (1) Ethyl 4-hydroxymethylpicolinate (2.00 g, 11 .0 mmol) was dissolved in dimethylformamide (80 ml). To the solu-

tion, imidazole (1.88 g, 27.0 mmol) and chloro-tert-butyldiphenylsilan (7.60 ml, 27.0 mmol) were added at room
temperature. The mixture was stirred for 2 hours at the same temperature. The reaction mixture was diluted with
hexane-ethyl acetate (1:1) and washed saturated brine and dried over magnesium sulfate. After filtration, the filtrate
was concentrated to afford a residue, which was purified by column chromatography on silica gel. The fraction

50 was eluted with hexane-ethyl acetate (95:5-70:30) to provide a crude compound (4.27 g) as colorless solid.

(2) The compound (3.14 g, 7.40 mmol) obtained in (1) was dissolved in methanol (60 ml). To the solution was
added hydrazine monohydrate (1.80 ml, 37.0 mmol) at room temperature. The mixture was stirred for 12 hours at
the same temperature. The reaction mixture was concentrated to afford a residue, which was dissolved in chloro-
form. The organic layer was washed with saturated brine and then concentrated to afford an oily compound, which

55 was used in the next reaction without further purification.

(3) The compound obtained in (2) was dissolved in chloroform (1 0 ml). To the solution was added 1 N hydrochloric
acid (22.2 ml, 22.2 mmol) at room temperature. The mixture was cooled in an ice-bath and sodium nitrite (1 .02 g,
1 4.8 mmol) was added at the same temperature. The mixture was stirred for 30 minutes at the same temperature.

151

EP 1 199 306 A1

The reaction mixture was extracted with chloroform. The organic layer was separated and washed with saturated
brine and dried over magnesium sulfate. After filtration, the filtrate was concentrated to afford a residue. To the
residue, asolution of the compound (0.622 g, 3.30 mmol) obtained in the reference example No. 3 in tetrahydrofuran
(50 ml) was added at room temperature. The reaction mixture was refluxed over night. The reaction mixture was

5 concentrated to afford a residue, which was purified by column chromatography on silica gel. The fraction eluted

with chloroform-tetrahydrofuran (10:0-9:1) provided the compound (2.03 g) as a brown amorphous.
(4) The compound (2.03 g, 3.30 mml) obtained in (3) was dissolved in tetrahydrofuran (1 0 ml). To the solution was
added a solution (6.60 ml) of n-butylammmonium fluoride (1 .0 M, 6.60 mmol) in tetrahydrofuran at room temper-
ature. The mixture was stirred for 1 hour at the same temperature. The reaction mixture was diluted with tetrahy-

10 drofuran, ethyl acetate and then washed with saturated brine. The organic layer was concentrated to afford light

yellow crystals by filtration. The filtrate was purified by column chromatography on silica gel. The fraction eluted
with chloroform -methanol (100:0-95:5) provided yellow crystals, which were combined with the crystal obtained
by filtration to afford the titled compound (1 .02 g).

1 H-NMR(DMSO-d 6 )S:1 .07-1 .20(1 H,m),2.31 -2. 44(2H,m),2.45-2. 58(1 H,m),3. 28-3.35(1 H,m),3. 50-3. 60(1 H,m),4.52
15 (2H,d, J=5.6Hz),4.83(1H,dd,J=10Hz,5.3Hz),5.47(1H,t,J=5.7Hz),6.99(1 H,d,J=4.7Hz),7.26(1 H,s),7.32(1 H,d,

J=7.5Hz), 7.47(1 H,t,J=7.8H z),8.23(1 H,d,J=5.3Hz), 8.33(1 H,d,J=7.6Hz),9. 96(1 H,s),1 1 .4(1 H ,br).
mass:339(M+1)+.

Working Example No.81

20

[0449] To a solution of the compound (3.50 g) of the reference example No. 5 in tetrahydrofuran (35 ml), a solution
(7.1 0 ml) of tetra-n- butylammonium fluoride solution (1 .0 M, 7.1 0 mmol) was added at room temperature. The reaction
mixture was stirred for 1 hour at the same temperature. The reaction mixture was concentrated and diluted with ether.
The whole was washed with water and saturated brine, and then dried over magnesium sulfate. After filtration the
25 filtrate was concentrated to afford a residue, which was washed with ether to afford the titled compound (1 .66 g) as
colorless solid.

1 H-NMR(DMSO-d 6 )5:1 .02-1 .22(1 H,m),2.26-2.31 (2H, brm),2. 46-2. 62(1 H,m), 2. 70(2H,t,J=6.3Hz),3. 22-3.40(1 H,m),
3.48-3.71 (3H,m),4.71 (1 H,brt),4.79-4.90(1 H,m),6.95(1 H,d, J=6.3Hz), 7.1 1 (1 H ,s), 7.30(1 H,d, J=6.3Hz),7.44(1 H,t,
J=7.9Hz),8.19(1H,d, J=6.3Hz),8. 30(1 H,d,J=7.9Hz),9. 86(1 H,s),1 1 .4(1 H,br).
30 mass:353(M+1)+.

Working Example No.82

[0450]

35

(1) The compound (45 mg, 0.13 mmol) of the working example No. 80 was dissolved in pyridine (1 ml). To the
solution, methanesulfonyl chloride (40 |_il, 0.52 ml) was added at room temperature. The reaction mixture was
stirred for 1 hour at the same temperature. The reaction mixture was made acidic by adding 1 N hydrochloric acid.
The mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran. The organic layer was washed with

40 1 N hydrochloric acid, saturated sodium hydrogencarbonate and saturated brine successively and then dried over

maganesium sulfate. After filtration, the filtrate was concentrated to afford a residue, which was dissolved in dimeth-
ylformamide (1 ml). To the solution sodium azide (85 mg, 1 .3 mmol) was added at room temperature. The reaction
mixture was stirred for 30 minutes at 80°C. The reaction mixture was diluted with chloroform and washed with
saturated brine. The organic layer was separated and concentrated to afford a light yellow solid (35 mg), which

45 was used for the next reaction without further purification.

(2) The compound (35 mg) obtained above in (1 ) was dissolved in a mixture (7 ml) of methanol and tetrahydrofuran
(5:2). To the solution, was added 1 0% palladium carbon catalyst (5 mg) at room temperature. The reaction vessel
was filled with hydrogen. The reaction mixture was stirred over night under the hydrogen atomosphere at room
temperature. The reaction mixture was filtrated through celite and the filtrate was concentrated. The crystals pre-

50 cipitated were collected by filtration to afford light yellow crystals (1 3 mg).

1 H-NMR(DMSO-d 6 )5:1.02-1 .1 0(1 H,m),2.21 -2.60(4H,m),3.45-3.52 (2H ! m) ! 4.06-4.09(2H,m),4.79-4.85(1 H,m),
5.1 6-5.20(1 H,m), 6.93(1 H,d,J=5.9Hz), 7. 20(1 H,s), 7.26(1 H,d,J=7.6Hz), 7.39-7. 45 (1 H : m),8.1 0(1 H,d,J=4.9Hz),8.27
(1 H,d,J=7.7Hz),1 0.3(1 H ,br),1 1 .7(1 H,br).
mass:338(M-i-1) + .

55

Working Example No.83

[0451] The compound (260 mg) of the reference example No. 9 was dissolved in a solution (1 0 ml) of methanol and

152

EP 1 199 306 A1

tetrahydrofuran (1:1). 1 0% palladium carbon catalyst (200 mg) was added to the solution at room temperature. The
reaction vessel was filled with hydrogen. The reaction mixture was stirred overnight under the hydrogen atomosphere
at room temperature. The insoluble material was filtered and the filtrate was concentrated to afford the titled compound
(105 mg).

5 1 H-NMR(DMSO-d 6 )5: 1.01-1 .22(1 H,m),2.28-2.40(3H,brm),2.62-2.72(2H,m),2.80-2.88(2H,m).3.1 8(2H,s), 3.45-3. 60

(2H,m), 4.82(1H,dd,J=9.8Hz,6.2Hz),6.95(1H,d,J=6.2Hz),7.12(1H,s), 7.30(1 H,d,J=6.8Hz),7.45(1 H,t,J=7.4Hz),8.20

(1H,d,J=5.5Hz), 8.30(1 H,d,J=6.2Hz),9. 94(1 H,br), 11. 4(1 H,br).

mass:352(M+1)+.

10 Working Example No.84

[0452]

(1) The compound (1 .02 g, 3.02 mmol) of the working example No. 80 was dissolved in a solution (90 ml) of dimeth-
15 ylformamide- tetrahydrofuran (1 :8). To the solution was added manganese dioxide (3.92 g, 45.1 mmol) at room

temperature. The reaction mixture was stirred for 6 hours at the same temperature. The reaction mixture was
filtrated by celite and filtrate was concentrated. The crystals precipitated were collected by filtration to afford yellow
crystals (0.211 g).

(2) The compound (34 mg, 0.10 mmol) obtained above in (1 ) and n-butylamine (22 mg, 0.30 mmol) were dissolved
20 in chloroform (5 ml). To the solution was added sodium triacetoxyborohydride (212 mg, 1 .0 mmol) at room tem-
perature. The reaction mixture was stirred for 24 hours at the same temperature. The reaction mixture was neu-
tralized with 3N hydrochloric acid and extracted with chloroform. The organic layer was washed with saturated
brine and dried over magnesium sulfate and then concentrated. The crystals precipitated were collected by filtration
to affod the titled compound (13 mg).

25 1 H-NMR(DMSO-d 6 )S:0.88(3H,t,J=7.3Hz),1 .08-1 .1 7(1 H,m),1 .28-1 .38(2H,m),1 .42-1 .51 (2H,m),2.31 -2.39(3H,m),

2.47-2.54 (2H,m),2.59(2H,t,J=7.2Hz),3.50-3.57(1 H,m),3.81 (2H,s), 4.83(1 H,dd,J=1 1 Hz,5.5Hz),7.09(1 H,d,
J=5.3Hz), 7.31 -7.33 (2H,m),7.47(1 H ,t,J=7.9Hz).8.26(1 H,d,J=5.3Hz),8.31 (1 H,d, J=8.1 Hz), 9.98(1 H ,s), 1 1 .2(1 H,br).
mass:394(M+1) + .

30 Working Examples No.85 to 94

[0453] According to the procedure described in working example No.84, the compounds from the working examples
No.85 to No. 94 were prepared.

35 Working Example No.85

[0454] 1 H-NMR(DMSO-d 6 )8:1 .1 1 -1 .1 8(1 H,m),2.22-2.44(5H,m),2.58(2H ) t, J=5.8Hz),3.46-3.58(3H,m),3.73(2H,s),
4.51 (1 H,t,J=5.4Hz), 4.84(1 H,dd,J=1 0Hz,5.6Hz), 7.05(1 H ,d,

J=5.4Hz), 7.26(1 H,s), 7.33(1 H,d,J=7.4Hz),7. 48(1 H,t,J=7. 9Hz), 8.24(1 H,d,J=5.3Hz), 8.34(1 H,d,J=8.2Hz), 9. 93(1 H,s),
40 11.4(1H,br).

mass:382(M+1)+.

Working Example No.86

45 [0455] 1 H-NMR(DMSO-d 6 )5:1 .06-1 .20(1 H,m),2.28-2.43(2H,m),2.48-2.60(1 H,m),3.00(1 H,br),3.28-3.40(1 H,m) ;

3.50-3.60(1 H,m), 3.71 (4H,s),4. 83(1 H,m), 7.06(1 H,d,J=4.6Hz), 7.25(1 H,d,J=7.4Hz) ,7.29-7.39(6H,m), 7.46(1 H,t,J=7.4Hz),

8.23(1 H,d,J=5.5Hz), 8.34(1 H,d,J=7.4Hz),9. 97(1 H,s), 11 .5(1 H,br).

mass:428(M+1)+.

50 Working Example No.87

[0456] 1 H-NMR(DMSO-d 6 )S:1 .06-1 .20(1 H,m), 2.29-2. 43(2H,m), 2.49-2. 60 (1 H,m),3.32(2H,s),3.49(2H,s),3.53-3.60
(1H,m),3.64(2H,s), 4.83(1H,dd,J=11Hz,5.6Hz),4.91(2H,s),6.51(2H ! d,J=8.3Hz), 6.99(1 H ,d,J=8.2Hz),7.04(2H,d,
J=5.4Hz), 7.26(1 H,s), 7. 32(1 H,d, J=7.4Hz), 7.47(1 H,t,J=7. 8Hz), 8.22(1 H ,d, J=5.4Hz),8. 33(1 H,d,J= 8.1 Hz), 9. 94(1 H,s),
55 11.5(1H,br).

mass:443(M-i-1) + .

153

EP 1 199 306 A1

Working Example No.88

[0457] 1 H-NMR(DMSO-d 6 )5:1 .07-1 .1 8(1 H,m), 2.32-2. 44(2H,m),2.51 -2. 66(5H,m),3. 28-3. 40(2H,m),3. 54-3. 61 (1 H,m),
3.72(2H,s), 4.82(3H,s),6.48(2H,d,J=8.2Hz),6.86(2H,d,J=8.2Hz),7.03 (1H,d, J=5.2Hz), 7.24(1 H,s),7. 32(1 H ; d,J=7. 3Hz),
7.48(1 H,t,J=7.6Hz),8 .22(1 H,d,J=5.0Hz),8.34(1 H,d,J=8.3Hz),9.94(1 H,s),1 1 .4(1 H,br).
mass:457(M+1) + .

Working Example No.89

[0458] 1 H-NMR(DMSO-d 6 )5:1 .12-1. 21(1 H,m), 2.33-2. 42(2H,m), 2.50-2. 59(2H,m),2. 90-3. 15(1 H,br),3. 51-3. 58(1 H,
m),3.70(2H,s), 3.77(2H,s), 4.84(1 H,dd,J=11 Hz, 5.6Hz), 7.08(1 H,d,J=5.3Hz), 7.28 7.46(4H,m), -7.48(1 H,t,J=7. 8Hz),
7.57(2H,d,J=8.2Hz), 7.79(2H, d,J=8.3Hz), 8.25(1 H,d,J=5.3Hz), 8.34(1 H,d, J=8.2Hz), 9.96(1H,s) ,11 .4(1 H,br).
mass: 507 (M+1) + .

Working Example No.90

[0459] 1 H-NMR(DMSO-d 6 )8:1. 08-1. 15(1 H,m), 2.30-2.57(5H,m), 2.71 -2.83(4H,m), 3.48-3.55(1 H,m), 3.71 (2H,s),
4.78-4.83(1 H,m), 6.99(1 H,d,J=5.3Hz), 7.23-7.25(3H,m), 7.30(1 H,d,J=7.6Hz), 7.39(2H,d,J=8.0Hz), 7.45(1 H,t,
J=7.8Hz), 7.71 (2H,d,J=7. 9Hz), 8. 20(1 H,d,J=4.9Hz), 8.31 (1 H,d,J=8.0Hz), 9.91 (1 H,s),1 1 .4(1 H,br).
mass:521(M+1)+.

Working Example No.91

[0460] 1 H-NMR(DMSO-d 6 )5:1 .05-1 .1 8(1 H,m), 2.26-2. 40(2H,m), 2.46-2. 60(2H,m),3. 00(1 H,br), 3. 50-3. 58(1 H,m), 3. 69
(2H,s),3.71 (2H,s),4. 82(1 H,dd, J=1 0Hz,5.9Hz), 7. 05(1 H,d,J=5.3Hz), 7.31 (2H, d, J=7.5Hz),7.38(2H,d,J=5.5Hz),7.46(1 H,
t,J=7.9Hz), 8.23(1 H,d, J=5.4Hz), 8.32(1 H,d,J=8.1 Hz),8.50(2H,d,J=5.9Hz),9.95(1 H,s),1 1 .4(1 H,br).
mass:429(M+1) + .

Working Example No.92

[0461] 1 H-NMR(DMSO-d 6 )8:1. 03-1.1 7(1 H,m),2.28-2.40(3H,m),2.47 ; 2.54 (1 H,m),2.73(4H,s),3.26-3.34(1 H,m),
3.50-3.58(1 H,m), 3. 70 (2H,s),4.80(1 H ; dd,J=1 1 Hz,5.6Hz),6.98(1 H,d,J=5.5Hz),7.23 (2H,d,J=6.1 Hz),7.23(1 H,s),7.29
(1H,d,J=6.6Hz),7.44(1H,t,J=7. 8Hz),8.1 9(1 H,d,J=5.3Hz),8.30(1 H,d,J=7.3Hz),8.42(2H,d,J=5.9H z),9.91 (1H,s),11 .4
(1H,br).

mass443(M+1)+.
Working Example No.93

[0462] 1 H-NMR(DMSO-d 6 )8:1 .05-1 .25(1 H,m), 2.27-2. 64(4H,m), 3.20-3. 41 (3H,m), 3.49-3. 60(2H,m),4.24(2H,brm),
4.84-4.92(1 H,m), 7.33-7. 63(6H ; m), 8.29(1 H ,d,J=7.7Hz), 8. 40(1 H,d,J=5.5Hz),9.08(1 H,s) ,9.85(2H,brm),1 0.3(1 H,s),
10.7(1H,brm).
mass:432(M+1) + .

Working Example No.94

[0463] 1 H-NMR(DMSO-d 6 )8:0.99-1 .14(5H,m),1 .75-1 .85(4H,m),2.25-2.38 (3H,m),2.47-2.55(1 H,m),3.26-3.35(2H,
m), 3. 48-3.57(1 H,m), 3.71 (2H,s),4.44(1 H,d,J=4.4Hz),4.81 (1 H,dd,J=1 0Hz, 5.6Hz),7.02(1 H,d,J=5.5Hz),7.23(1 H,s),7.29
(1 H,d,J=7.4Hz),7.4 5(1 H,t,J=7.7Hz),8.1 9(1 H ,d,J=5.3Hz),8.30(1 H,d,J=8.2Hz),9.90( 1 H ; s),11 .4(1 H,br).
mass:436(M+1)+.

Working Example No.95

[0464] According to the procedure described in working example No. 96, tert-butyl N-(2-aminoethyl) carbamate was
used to afford the titled compound.

1 H-NMR(DMSO-d 6 )5: 1.01-1 .1 5(1 H,m), 2. 25-2. 61 (3H,brm),2. 97-3. 03(2H,brm), 3.1 4-3.35(6H,brm),3. 50-3. 59(1 H,m),
3.80-4.00 (1 H, brm),4. 80-4. 86(1 H,m), 7. 05(1 H,brd), 7.25-7. 34(2H,m), 7.46(1 H,dd),8.21 -8.30(4H ! m),9.48(2H,br),1 0.2
(1H,brs),10.9 (1H,br).
mass:395(M-i-1) + .

154

EP 1 199 306 A1

Working Example No.96
[0465]

5 ("I) A solution of 4-nitrobenzenesulfonylchloride (844 mg, 3.81 mmol) in chloroform (9 ml) was cooled in an ice-

bath. Triethylamine (0.531 ml, 3.81 mmol) was added to the solution. The reaction mixture was warmed up to room
temperature. A solution (0.3ml) of n-propylamine (1 0 jxl, 0.122 mmol) in chloroform was added to the solution (0.3
ml) at room temperature. The reaction mixture was stirred overnight at the same temperature. The reaction mixture
was purified by TLC eluted with chloroform-methanol(1 9:1 ) to afford the titled compound.

10 (2) To the compound obtained in (1), a solution of the compound (38 mg) of the reference example No. 7 and

triphenylphosphine (29 mg, 0.111 mmol) in chloroform (0.6 ml) was added. A40% solution (0.047ml, 0.108 mmol)
of diethylazodicarboxylate in toluene was added to the reaction mixture. The reaction mixture was stirred for 3
days at room temperature. The reaction mixture was purified by TLC eluted with chloroform-methanol (19:1) to
afford the titled compound.

15 (3) The compound obtained in (2) was dissolved in dimethylformamide (1 ml). To the solution, sodium carbonate

(35 mg, 0.330 mmol) and thiophenol (11 uJ, 0.107 mmol) were added at room temperature. The reaction mixture
was stirred for 1 day at the same temperature. The insoluble material was filtated and the filtrate was dissolved in
tetrahydrofuran (3 ml). To the reaction mixture, 1 N hydrochloric acid (1 ml) was added at room temperature. The
whole was stirred for one hour at room temperature. The reaction mixture was concentrated to provide a residue,

20 which was boiled with toluene by heating. To the mixture, methanol-ether was added to afford the titled compound.

1 H-NMR(DMSO-d 6 )5:0.93(3H,t,J=7.5Hz), 1 .03-1 .1 7(1 H,m), 1 .58-1 .70(2H,m), 2.26-2.40(2H,brm), 2.55-2.65(1 H,
brm), 2.85-2.95 (2H,brm), 2.96-3.03(2H,m), 3.12-3.22(2H,brm), 2.28-2.35(1 H, m), 3. 50-3. 60(1 H,m),4.80-4. 86(1 H,
m),7.06(1H,d,J=5.2Hz),7.30-7.35(2H,m),7.48(1H,t,J=7.9Hz),8.27-8.32(2H,m),8.86(2H, br),1 0.4(1 H,brs),1 0.9(1 H.
br).

25 mass:394(M+1)+.

Working Examples No.97 and 98

[0466] According to the procedure described in the working example No.96, the compounds of the working example
30 No.97 and No. 98 were prepared.

Working Example No.97

[0467] 1 H-NMR(DMSO-d 6 )S:0.89(3H,t,J=7.8Hz), 1.01-1 .1 7(1 H,m), 2. 26-2. 40(2H,m), 2.52-2. 63(2H,m),2.26-2.39(2H,
35 m), 2. 50-2.61 (1 H,m),2. 88-3. 00(4H,m), 3.1 0-3.21 (2H,m),3.26-3.34(1 H,m), 3.50-3.60(1 H,m),4. 80-4. 86(1 H ,m), 7. 02(1 H,
d,J=4.6Hz),7.26-7.34(2H J m),7.46(1H,t,J=7.8Hz),8.26-8.30(2H,m),8.80(2H,m), 1 0.2(1 H,s),1 1 .0(1 H,br).
mass:408(M-i-1) + .

Working Example No.98

40

[0468] 1 H-NMR(DMSO-d 6 )5:0.86(3H,t),1 .00-1 .20(1 H,m),1 .21 -1 .34 (4H,m),1 .54-1 .66(2H,m),2.26-2.38(2H,m),2.40-
2.63(1 H,m), 2. 85-3. 00(4H,m), 3. 08-3. 23(2H,m),3. 26-3.35(1 H,m), 3. 50-3. 60 (1 H, m),4. 80-4. 86(1 H ,m), 7. 03(1 H,d,
J=4.3Hz),7.26-7.35(2H,m) ; 7.46(1 H,t,J=7.8Hz),8.26-8.30(2H ,m), 8.81 (2H, brm), 1 0.3(1 H,s), 1 1 .0(1 H,br).
mass:422(M+1)+

45

Working Example No.99

[0469] According to the procedure described in the working example No.96, glycolaldehydediethylacetal was used
to afford the titled compound.

50 1 H-NMR(DMSO-d 6 )5: 1.05-1 .1 5(1 H,m), 2. 25-2. 40(3H,m), 2.43-2. 63 (1 H,m),2. 90-3.37(6H,m),3. 48-3. 60(1 H,m), 4.77-
4.85(1 him), 6.97-7.02(1 H,m), 7. 23-7.34(2H,m), 7. 40-7.50(1 H, m), 8.23-8. 32(2H,m), 8. 66(0. 5H, brm), 9. 00-9.23(1 H, brm),
10. 1(11-1, s), 11.0(1H,br).
mass:394(M-i-1) + .

55 Working Example No.1 00

[0470] According to the procedure described in the working example No.96, glycine tert-butyl ester was used to
afford the titled compound.

155

EP 1 199 306 A1

1 H-NMR(DMSO-d 6 )S:1. 03-1.1 0(1 H,m), 2. 23-2. 40(2H,brm),2. 54-2. 65(1 H,brm), 2. 97-3. 05(2H,brm),3.1 7-3.40(3H,m),
3. 50-3.59(1 H,m), 3. 94(2H,brs), 4. 81 -4.86(1 H,m), 7. 03(1 H,d,J=5.5 Hz),7.28-7.34(2H,m),7.46(1 H,t,J=7.8Hz),8.26(2H,d,
J=6.5Hz), 9.23(2H,br),1 0.4(1 H,br),1 0.9(1 H ; br).
mass:466(M-i-1) + .

Working Examples No.101 to 108

[0471] According to the procedure described in the working example No. 96, the compounds from the working ex-
ample No.101 to 108 were prepared.

Working Example No.101

[0472] 1 H-NMR(DMSO-d 6 )5:1 .03-1 .15(1 H,m), 2.25-2. 63(3H,m),2. 95-3. 05 (2H,m),3.1 9-3.37(3H,m),3.50-3.61 (1 H,

m),4.1 0-4.1 9(2H,m), 4.80-4.86(1 H,m),5.26(2H,s), 7. 00(1 H,d,J=5.5Hz), 7. 28 7.49(8H,m),8.26-8.32(2H,m),9.37(2H,
brm),10.2(1H,s),10.9 (1H,br).
mass:500(M-i-1) + .

Working Example No.1 02

[0473] 1 H-NMR(DMSO-d 6 )8:1 .03-1 .1 7(1 H,m), 2.26-2. 63(3H,brm),2. 97-3. 05(2H,brm),3.1 0-3.21 (2H,brm),3. 26-3. 37
(1 H,brm),3.50-3.60(1 H,m),3.78(3H,s), 4. 06-4.1 7(2H,brm), 4. 80-4.88(1 H,m), 6.98-7.03(3H,m),7.26(1 H,brm),7.34(1 H,d,
J=8.3Hz),7.43-7.50(3H,m) ! 8.25-8.30(2H,m),9.18(2H,brm),10.3(1H,brs), 1 0.9(1 H,br).

Working Example No.1 03

[0474] 1 H-NMR(DMSO-d 6 )5:1 .02-1 .1 8(1 H ) m) ) 2.25-2.40(3H,m) J 2.44-2.63(2H J m),3. 06-3. 09(2H 5 m) 5 3.25-3.35(3H,m) )
3.50-3.59 (1H,m),4.82-4.88(1H,m),7.04(1H,dd,J=6.0Hz,1 .1 Hz),7.30-7.35(2H,m) ) 7.45-7.55(3H,m),7.92(1 H,t),8.28
(2H,d,J=7.0 Hz),8.67(1H,m),9.39(2H,brm),1 0.4(1 H,brm),1 0.9(1 H,br).
mass:443(M+1)+.

Working Example No.1 04

[0475] 1 H-NMR(DMSO-d 6 )5:1 .01 -1 .15(1 H,m), 2.30-2. 40(3H ) m),2.41 -2.56 (1 H,m), 2.57-2. 64(1 H^)^. 04-3. 11 (2H,
m),3.20-3.36(3H,m), 3.50-3.59(1 H,m), 4. 82-4. 87(1 H,m), 7. 07(1 H,d,J=6.6Hz), 7.31 -7.35(2H,m),7.48(1 H,t,J=7.8Hz),
7.83-7.90(1 H,m), 8. 25-8.29 (2H,m), 8.46(1 H,d),8.83(1 H.dd,J=5.3Hz,1 .3Hz),8.98(1 H,s),9.79 (2H,brm),1 0.3(1 H,br)
110.9(1H,br).
mass:443(M-i-1) + .

Working Example No.1 05

[0476] 1 H-NMR(DMSO-d 6 )5:1 .03-1 .1 7(1 H,m), 2.26-2. 40(2H,m),2.50-2. 65 (1 H,m),3.05-3.15(2H,m),3.21-3.37(3H,
m), 3. 50-3.61 (1 H,m), 4.40-4.45(2H,m),4.81 -4.89(1 H,m),7.05(1 H,d,J=4.6Hz),7.25-7.35(2H,m),7.46(1 H,t,J=8.3Hz),
7.99(2H,d,J=7.4Hz),8.28(2H,d, J=7.4Hz),8.86(2H,d,J=6.5Hz), 9.90-1 0.0(2H,m),1 0.3(1 H,s), 10.9(1 H,br).
mass:443(M-i-1) + .

Working Example No.1 06

[0477] 1 H-NMR(DMSO-d 6 )5:1 .03-1 .17(1 H,m), 2.25-2. 37(2H,m), 2.40-2. 60(1 H,m),2. 91-3. 01 (4H ) m),3.1 4-3.35(5H,m),
3.49-3.59 (1 H,m),4. 80-4. 85(1 H,m), 7.02(1 H,d,J=5.3Hz), 7.26-7.37 (7H,m), 7.46(1 H ,t),8.26-8.29(2H,m),8.94(2H,brm),
10.2(1H, s),11.0(1H,br).
mass:456(M-i-1) + .

Working Example No.1 07

[0478] 1 H-NMR(DMSO-d 6 )8:1 .03-1 .1 7(1 H,m), 2.26-2. 50(3H,brm),2. 54-2. 63(1 H,brm),2.83(2H,t),3.00(2H,t) )

3. 06-3.23(3H,brm),3.26-3. 37(1 H,m), 3.50-3. 58(1 H,m),4. 80-4. 86(1 H,m), 6. 72(2H,d, J=8.3Hz),7.05(3H ! d,J=8.3Hz),

7. 28-7.35(2H,m), 7.46(1 H,t,J= 7. 8Hz), 8.26-8. 32(2H,m), 8. 94(2H, brm), 1 0.3(1 H,s),1 1 .0(1 H,br).

mass:472(M+1)+.

156

EP 1 199 306 A1

Working Example No.1 08

[0479] 1 H-NMR(DMSO-d 6 )d:1 .05-1 .15(1 H,m),2.26-2.40(2H,brm), 2.43-2. 63(2H,brm),2. 98-3. 06(2H,m), 3. 20-3. 43(6H,
brm),3.50-3.65 (1 H,m),4. 81 -4.88(1 H,m),7.03(1 H ; d,J=5.5Hz),7.30-7.35(2H,m),3.45-3.50(1 H,m),7.95(2H,d,J=5.5Hz),
5 8.28(2H,d, J=5.5Hz),8.86(2H,d ; J=5.5Hz),8.72(2H,brm) ) 10.2(1H ) s),10.9(1H ,br).
mass:457(M-i-1) + .

Working Example No.1 09

10 [0480] According to the procedure described in the reference example No. 8, the titled compound (80 mg) was ob-
tained.

1 H-NMR(DMSO-d 6 )5:1.03-1 .25(2H,m), 2.26-2. 43(2H,brm), 2.50-2.65(1 Km), 2.57(6H,s),2.88-3.06(3H,m) ! 3.26-3.40
(1H,m), 3.50-3.59(1 H,m), 4.82-4.86(1 H,m), 7.00(1 H,d,J=5.5Hz), 6.26-6.34 (2H,m), 7.46(1 H,t,J=7.8Hz), 8.23(1 H,d,
J=5.5Hz), 8.30(1 H,d,J=8. 3Hz), 1 0.0(1 H,s),1 0.5(0. 5H,br), 1 1 .1 (1 H,br).
15 mass:380(M+1)+.

Working Example No.1 1 0

[0481] To a solution of the compound (30 mg, 0.038 mmol) of the reference example No.11 in chloroform (1 ml), n-
20 butanoylchloride (6uJ, 0.058 mmol) and triethylamine (13jx 1 , 0.093 mmol) were added at room temperature. The re-
action-mixture was stirred for 1 hour at the same temperature. To the reaction mixture, n-butanoyl chloride (6uJ , 0.058
mmol) and triethylamine (10(xl, 0.072 mmol) were added at room temperature. The reaction mixture was stirred for 10
minutes atthe same temperature. To the reaction mixture, water (1 ml) was added and the organic layer was separated.
The organic layer was washed with water (1 ml) and dried over magnesium sulfate. After filtration, the filtrate was
25 concentrated to give a residue, which was dissolved in tetrahydrofuran (1 ml). To the mixture, 1 N hydrochloric acid (1
ml) was added at room temperature. The reaction mixture was stirred for 15 minutes at the same temperature. The
reaction mixture was concentrated to afford a residue, to which methanol-ether was added. The titled compound pre-
cipitated was obtained.

1 H-NMR(DMSO-d 6 )5:0.80(3H,t,J=7.8Hz),1 .03-1 .15(1 H,m),1 .42-1 .54(2H,m),2.00(2H ; t,J=6.9Hz),2.25-2.40(2H,brm),
30 2.55-2.63 (1H,brm),2. 70-2. 78(2H,brm), 3.28-3. 39(3H,brm), 3. 50-3. 60(1 H, brq),4. 80-4. 86(1 H,m), 7.01 (1 H ! d,J=4.6Hz),
7.1 4(1 H,s), 7.34 (1H ; d,J=8.3Hz), 7.48(1 H,t,J=7.8Hz),7.88(2H,brm), 8. 23(1 H,d,J= 4.6Hz),8.26(1 H,d,J=8.3Hz),1 0.4(1 H,
br),11.1(1H,br).
mass:422(M+1) + .

35 Working Examples No.1 11 to 114

[0482] According to the procedure described in the working example No. 110, the compounds from the working ex-
ample No.1 11 to 114 were prepared.

40 Working Example No.1 1 1

[0483] 1 H-NMR(DMSO-d 6 )8:1 .00-1 .23(1 H,m), 2.26-2. 60(3H,m),2.70(2H, br),3.1 5(2H,br),3.40-3.60(2H,m),4.34(2H,
s), 4. 80-4. 90(1 H, m),6.97(1 H, d,J=4.9Hz), 7.1 5(1 H, s), 7.30(1 H,d, J=8.0Hz),7.40-7.52(6H,m),8. 23(1 H,d,J=4.3Hz),8.30
(1 H,d,J=8.0Hz),8.54-8.63(1 H,m) ! 9.94(1 H,s),1 1 .4(1 H,br).
45 mass:470(M+1)+

Working Example No.1 12

[0484] 1 H-NMR(DMSO-d 6 )S:1 .00-1 .20(1 H,m), 2.26-2. 40(2H,m),2.41 -2.60(1 H,m),2.83(2H,brt),3.1 5(1 H,s),3. 20-3.40
50 (1H,m), 3.43-3. 57(2H,m),4.75-4. 86(1 H,m),6.97(1 H,d,J=7.6Hz),7.1 5(1 H,s), 7.30(1 H,d,J=1 1 Hz),7.40-7.52(4H,m),7.80
(2H,d,J=10Hz),8.21 (1 H,d,J=6.7Hz), 8.30(1 H,d,J=1 1 Hz),8.59(1 H,brt), 9.94(1 H,s) ; 1 1 .4(1H,br).
mass:456(M+1) + .

Working Example No.1 13

55

[0485] 1 H-NMR(DMSO-d 6 )5:1 .06-1 .20(1 H,m), 2.25-2. 41 (2H,m),2.72(2H, t),3.1 0-3.20(2H,m),3.26-3.42(1 H,m),3.48-
3.60(1H,m),3.75-3.90(1H,m),4.36(2H,s),4.80-4.86(1H,m),6.99(1H,d,J=5.7Hz), 7.13(1 H,s),7.1 9-7.40(7H,m), 7. 46(1 H,
t,J=7.6Hz),8.23(1 H,d, J=3. 8Hz), 8. 28(1 H,d,J=8.6Hz), 10.0(1 H,s),1 1 .2(1 H,br).

157

EP 1 199 306 A1

Working Example No.114

[0486] 1 H-NMR(DMSO-d 6 )5:1 .43-1 .60(1 H,m), 2.50-3. 00(3H,brm),3. 03-3.1 5(2H,brm),3. 34-3. 48(2H,brm),3. 65-3. 80
(1 H,brm),3. 85-4. 00(1 H,m),5.1 7-5.26(1 H,m),7.31 (1 H,d,J=5.4Hz),7.46(1 H, s),7. 72(1 H,dd,J=6.8Hz,0. 6Hz),7. 87(1 H,t),
5 7.94-8.03(3H, m),8.1 0-8.20(3H,m),8.58(1 H,d, J=4.7Hz),8.70(1 H,dJ=8. 1 Hz), 1 0.4(1 H,s),1 1 .7(1 H,br).
mass:492(M+1)+.

Working Example No.115

10 [0487] According to the procedure described in the working example No. 96(1 ), the compound of the working example
No. 83 was used to afford the titled compound.

1 H-NMR(DMSO-d 6 )5:1 .04-1 .1 9(1 H,m),2.26-2.41 (2H,m), 2.48-2. 60(1 H,m),2. 66-2. 74(2H,m), 3.1 0-3.20(2H,m),
3.28-3.39 (1 H,m),3.51 -3.59(1 H, m),4. 79-4. 82(1 H,m), 6. 90(1 H,d,J=4.6Hz), 7.01 (1 H,s), 7.32(1 H,d, J=8.3Hz),7. 46(1 H,t,
J=8.3Hz),7.97 (2H,d,J=9.2Hz),8.17(2H,m),8.29-8.37(3H,m),9.90(1H,s),11 .2 (1H,br).
15 mass:537(M+1)+.

Working Example No.1 1 6

[0488] According to the procedure described in the working example No. 56, phenol and the compound of the refer-
ee ence example No. 7 were used to afford the compound, which was subjected to the similar manner to that described
in the working example No. 1 24 to provide the titled compound.

1 H-NMR(DMSO-d 6 )8:1. 08(1 H,t,J=7.4Hz),2.25-2.40(2H,m), 2. 60-2. 69(1 H,m),3.1 0(2H ; t,J=5.5Hz), 3. 25-3. 35(1 H,m),
3.54(1 H,q, J=9.2Hz),4. 25(2H,t,J=5.5Hz),4. 80-4.86(1 H, m), 6. 92(1 H,d, J=12Hz),6.94(2H,d,J=7.4Hz),7.20(1 H,d,
J=5.5Hz), 7.25-7.37 (4H,m),7. 48(1 H,t,J=7.4Hz),8.23-8.28(2H ,m), 1 0.5-1 1 .0(2H ; br).
25 mass: 429 (M+1) + .

Working Example No.1 1 7

[0489]

30

(1) To a solution of 3-amino-5-phenylpyrazole (544 mg, 3.4 mmol) in dimethylformmamide (10 ml) , sodium hydride
(64 mg, 4.1 mmol), benzylchloride (0.45 ml, 3.8 mmol) were added at room temperature. The reaction mixture was
stirred for 6 hours at room temperature. Saturated aqueous ammonium chloride was added and extracted with
ethyl acetate. The organic layer was separated and washed with water and saturated brine and dried over magen-

35 isum sulfate. After filtration, the filtrate was concentrated to afford a residue, which was purified by column chro-

matography on silicagel.Thefraction elutedwith hexane-ethyl acetate (4:1) provided thetitled compound (509 mg).

(2) To a solution of the compound (509 mg. 2.0 mmol) obtained in (1) in pyridine (5.0 ml) was added methyl
chloroformate (0.19 ml, 2.5 mmol) at room temperature. The mixture was stirred for 2 hours at room temperature.
To the reaction mixture, 1 N hydrochloric acid was added. The mixture was extracted with ethyl acetate. The organic

40 layer was separated and washed with saturated sodium hydrogencarbonate, saturated brine and then dried over

magnesium sulfate. After filtration, the filtrate was concentrated to afford a residue, which was purified by column
chromatography on silica gel. The fraction eluted with hexane-ethyl acetate (4:1-2:1) provided thetitled compound
(450 mg).

(3) To a solution of the compound (440 mg, 1 .4 mmol) obtained in (2) in toluene (5.0 ml), triethylamine (0.40 ml,
45 2.9 mmol) was added. The mixture was stirred for 10 minutes at 80°C. B-chlorocatecolboran (450 mg, 2.9 mmol)

was added and the mixture was stirred for 1 0 minutes at the same temperature. The compound (290 mg, 1 .5 mmol)
of the reference example No. 3 was added and the mixture was stirred for 30 minutes at the same temperature.
B-chlorocatecolboran (440 mg, 2.9 mmol) was added and the mixture was stirred for 1 hour at 100 °C. To the
reaction mixture 1 N hydrochloric acid was added. The mixture was extracted with chloroform. The organic layer
50 was separated and washed with 1N sodium hydroxide, saturated brine and dried over magnesium sulfate. After

filtration, the filtrate was concentrated to afford a residue. To the residue, was added chloroform-etherto afford the
crystal (400 mg) by filtration.

(4) The compound (400 mg, 0.87 mmol) obtained in (3), was dissolved in methanol-tetrahydrofuran (1 :1 , 20 ml).
1 0% paradium carbon catalyst (200 mg) was added. The reaction vessel was filled with hydrogen and the mixture

55 was stirred overnight at 50 °C. The reaction mixture was filtrated by celite. The filtrate was concentrated to afford

a residue. To the residue, ether-ethyl acetate was added to provide cystals as the titled compound (220 mg).
1 H-NMR(DMSO-d 6 )5:1.02-1 .1 0(1 H,m), 2.27-2. 37(2H,brm),2. 62-2. 67(1 H,brm), 3.26-3.37(1 H,m),3.48-3. 57(1 H,m),
4.75(1 H,dd, J=1 1 Hz, 5. 7Hz),6. 60(1 H, brs), 7.28(1 H,d,J=7.5Hz), 7. 30-7.48 (4H,m),7.73(2H,d,J=7.3Hz),8.26(1 H,d,

158

EP 1 199 306 A1

J=8.2Hz),9.61(1H,s),12. 8(1H,br).
Working Example No.11 8
5 [0490]

(1) A mixture of a-cyano-o-iodoacetophenone (3.81 g, 13.3 mmol), benzylhydrazine 2 hydrogen chloride (7.80 g,
40.0 mmol), triethylamine (18.0 ml, 129 mmol) and n-butanol (50 ml) was stirred overnight at 120 °C. The raction
mixture was cooled to room temperature and concentrated to afford a residue. The residue was dissolved in ether.

10 The solution was washed with water and then dried over magnesium sulfate. After filtration, the filtrate was con-

centrated to afford a residue, which was purified by column chromatography on silica gel. The fraction eluted with
hexane-ethyl acetate (5:1-2:1) provided the compound (2.61 g) as light yellow crystals.

(2) A mixture of the compound (1.23 g, 3.27 mmol) obtained in (1), p-nitrophenyl chloroformate (0.859 mg, 4.26
mmol), 4-dimethylaminopyridine (1.00 g, 8.19 mmol) and chloroform (10 ml) was stirred for 30 minutes at room

*s temperature. To the reaction mixture, the compound (0.920 g, 4.96 mmol) prepared in the reference example No.

3 was added. The reaction mixture was stirred overnight at 1 00 °C. The reaction mixture was diluted with chloro-
form. The whole was washed with 1N sodium hydroxide, 1N hydrochloric acid and saturated brine respectively
and then dried over magnesium sulfate. After filtration, the filtrate was concentrated to afford a residue, which was
purified by column chromatography on silica gel. The fraction eluted with chloroform-methanol (98:2-97:3) provided

20 yellow solid (1.60 g).

(3) The compound (236 mg, 0.461 mmol) obtained in (2), pallolium acetate (11 mg, 0.0490 mmol), 1 ,1 -bis(diphe-
nylphosphino)ferrocene (30 mg, 0.0541 mmol) and sodium hydrogencarbonate (71 mg, 0.845 mmol) were mixted
with methanol (4 ml) and the reaction vessel was filled with carbon monoxide. The reaction mixture was refluxed
for 7 hours. The reaction mixture was filtrated by celite. The filtrate was concentrated to afford a residue, which

25 was purified by column chromatography on silica gel. The fraction eluted with chloroform-methanol (98:2-97:3)

provided a yellow solid (1 80 mg).

(4) The compound (40 mg) obtained above in (3) was dissolved in ethanol (5 mW). To the solution, palladium
hydroxide (10 mg) was added at room temperature. The reaction vessel was filled with hydrogen. The reaction
mixture was stirred overnight at 70 °C. The reaction mixture was filtered through celite. The filtrate was concentrated

30 to afford a residue, which was purified by column chromatography on silica gel. The fraction eluted with chloroform-

methanol (10:1) provided the titled compound (8.6 mg).

1 H-NMR(DMSO-d 6 )8:1.03-1 .1 5(1 H,m), 2.25-2. 40(2H,m),2. 62-2. 77(1 H,m),3.43-3.58(2H ,m),3.73(3H,s), 4. 74-4. 78
(1 H,m), 6.25(1 H,m), 7.27(1 H ; d,J=7.6Hz),7.41 -7.74(5H,m), 8.23-8. 26 (1 H,m),8.31 (1 H,s),9.59(1 H,s).
mass:432(M+1)+.

35

Working Example No.11 9
[0491]

40 (1) The compound (140 mg, 0.268 mmol) obtained from the working example No.1 1 8(3) was dissolved in methanol

(3 ml). To the solution was added 1 N sodium hydroxide (1 .00 ml, 1 .00 mmol) at room temperature. The reaction
mixture was stirred for a while at room temperature and furtherly stirred for 2 hours at 50 °C. The reaction mixture
was made acidic by adding 1N hydrochloric acid. The whole was concentrated to afford a residue, which was
dissolved in chloroform. The solution was washed with water. The aqueous layer was further extracted with chlo-

45 roform twice. The organic layers were combined and dried over magnesium sulfate. After filtration, the filtrate was

concentrated to afford a residue. Adding ether and chloroform to the residue resulted in theformation of the crystals.
After filtration, the crystals (73 mg) were collected.

(2) The compound (36 mg, 0.0699 mmol) obtained above in (1) was dissolved in ethanol (4 ml). To the solution,
palladium hydroxide (10 mg) was added. The reaction vessel was filled with hydrogen and the reaction mixture

50 was stirred overnight at 70 °C. The reaction mixture was filtrated by celite. The filtrate was concentrated to afford

a residue. Ether and chloroform were added to the residue to afford the titled compound (13 mg) as crystals.
1 H-NMR(DMSO-d 6 )S:1.01-1 .1 4(1 H,m), 2.25-2. 34(2H,m),2. 65-2. 68(1 H,m),3.35-3.53(2H ,m),4. 74(1 H,dd,J=1 0Hz,
5.8Hz), 6.34(1H,br),7.27(2H ! d,J=7.5Hz),7.43(2H,t,J=7.8Hz),7.54(1H,d ,J=3.8Hz),7.70(1 H,d,J=7.4Hz),8.26(1 H,d,
J=8.1 Hz), 9.59(1 H,s).

55 mass:418(M+1) + .

159

EP 1 199 306 A1

Working Example No.120
[0492]

5 (1) According to the procedures described in the working example No. 11 8(1 ) to (3), a-cyano-m-iodoacetophenone

was used to afford the compound, which was furtherly subjected to the reaction described in the working example
No. 11 9(1) to afford the titled compound.

(2) According to the procedure described in the working example No. 11 9(2), the compound obtained in (1) was
used to afford the titled compound.
10 1 H-NMR(DMSO-d 6 )5:1 .02-1 .1 7(1 H, m), 2.25-2. 40(1 H,m),2. 63-2. 72(2H,m),3. 34-3.41 (2H,m),4. 74-4. 80(1 H,m),6.65

(1H,br), 7.28(1 H,d,J=7.6Hz),7.44(1 H,t,J=7.6Hz), 7.58(1 H,t,J=7.7Hz),7. 91 (1 H,d,J=8.0Hz), 7.97(1 H ; d,J=7.9Hz),
8.25(1 H,d,J=8.2Hz), 8.30 (1 H,d,J=4.3Hz),9.68(1 H,s).
mass:418(M+1) + .

15 Working Example No.121

[0493]

(1 ) The compound (56 mg, 0.1 1 mmol) obtained from the working example No. 1 20 was dissolved in dimethylfor-
20 mamide (1 .5 ml). To the solution, 1 ,1 -dicarbonyldiimidazole (25 mg, 0.15 mmol) was added at room temperature.

The reaction mixture was stirred for 30 minutes at room temperature. To the mixture phenylethylamine (42 uJ, 0.33
mmol) was added at room temperature and the mixture was heated from room temperature to 70 °C and furtherly
stirred for 1 0 minutes. The reaction mixture was concentrated to afford a residue, which was purified by thin layer
chromatography. The elution with chloroform-methanol (10:1) provided a crude compound, which was used for
25 the next reaction without further purification.

(2) The compound (51 mg, 0.084 mmol) obtained above in (1 ) was dissolved in methanol-tetrahydrofuran (2:1) (3
ml). To the solution was added paradium hydroxide (51 mg) at room temperature. The reaction vessel was filled
with hydrogen and the reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered
by celite. The filtrate was concentrated to afford the titled compound (25 mg).

30 1 H-NMR(DMSO-d 6 )5:1 .02-1 .1 0(1 H,m), 2.25-2. 36(2H,m), 2.43-2.56 (1 H,m), 2.65(2H,t,J=7.1 Hz), 2.87(2H,t,

J=7.5Hz), 3.16-3.25 (2H,m), 4.73-4.79(1 H,m), 6.70(1 H,br), 7.1 6-7.33(7H,m), 7.44 (1 H,t,J=7.9Hz), 7.54(1 H,t,
J=7.7Hz), 7.79(1 H,d,J=7.0Hz), 7.87(1 H,d,J=6.3Hz), 8,1 9(1 H,s),8.26(1 H,d,J=7.7Hz), 8.72(1 H,br), 9.69 (1H,br).
mass:521(M+1)+.

35 Working Example No.122

[0494]

(1 ) According to the procedure described in the reference example No. 2(1 ), 2-bromo-3-nitrobenzoic acid (1 0.0 g,
40 40.7 mmol), pyrrole-2-carboxy aldehyde (7.74 g, 81 .4 mmol), triethylamine (20.0 ml, 1 43 mmol) and thionyl chloride

(30 ml) were used to provide the titled compound (9.07 g).

(2) A solution of the compound (9.07 g, 28.0 mmol) obtained above in (1 ) in tetrahydrofuran (400 ml) was cooled
to -78 °C. To the solution, a solution (33.6 ml) of diisopropylammonium hydride (1 .0 M, 33.6 mmol) in toluene was
added at the same temperature. The reaction mixture was stirred for 2 hours at the same temperature. To the

45 reaction mixture was added asaturated aqueous ammonium chloride (15 ml) atthesametemperature. The reaction

mixture was warmed up to room temperature and stirred for 2 hours. The organic layer was separated and dried
over magnesium sulfate. After filtration, the filtrate was concentrated to afford a residue, which was dissolved in
methylene chloride (200 ml). To the solution was added chloro-tert-butyl dimethylsilan (6.32 g, 41 .9 mmol) and
imidazole (3.80 g, 55.8 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mix-
so ture was diluted with ethyl acetate. The organic layer was washed with water (200 ml) for 3 times and saturated
brine respectively and then dried over magnesium sulfate. After filtration, the filtrate was concentrated to afford a
residue, which was purified by column chromatography on silica gel (Wakogel C-300). The fraction eluted with
hexane-ethyl acetate (10:1-5:1) provided a colorless oily compound (9.34 g).

(3) The compound (9.34 g, 21 .3 mmol) obtained above in (2) and diisopropylethylamine (8.24 g, 63.8 mmol) were
55 dissolved in dimethyl formamide (200 ml). The reaction vessel was filled with nitrogen. To the reaction mixture

tetrakistriphenylphosphine palladium (2.46 g, 2.13 mmol) was added. The reaction mixture was stirred for 2 hours
at 130 °C. The reaction mixture was added ethyl acetate (1 L) and water (500 ml). The organic layer was separated.
The aqeouse layer was further extracted with ethyl acetate (300 ml). The combined organic layers were washed

160

EP 1 199 306 A1

with water and saturated brine respectively and dried over magnesium sulfate. After filtration, the filtrate was con-
centrated to afford a residue, which was purified by column chromatography on silica gel (wakogel C-300). The
fraction eluted with hexane-ethyl acetate (20:1-5:1) provided a yellow solid compound (4.73 g).

(4) The compound (4.73 g, 13.2 mmol) obtained above in (3) was dissolved in methanol-tetrahydrofuran (1:1) (400
5 ml). To the solution was added 1 0% palladium carbon catalyst (500 mg) at room temperature. The reaction vessel

was filled with hydrogen. The whole was stirred for 2 hours at room temperature. The reaction mixture was filtrated
by celite. After filtration, the filtrate was concentrated to afford a residue, which was purified by column chroma-
tography on silica gel (Wakogel C-300). The elution with hexane-ethyl acetate (2:1-1 :1) provided fraction 1 (less
polar compound) as pyrrole compound (1 .20 g) and fraction 2 (more polar compound) as pyrrolidine compound
10 (2.40 g).

Fraction 1 (less polar compound)

1 H-NMR(CDCI 3 )8:0.14(6H,s),0.95(9H,s),3.84(2H ! brs), 4.88(2H,s),5.98(1 H,d,J=3.1 Hz), 6. 09-6.1 1 (1 H,m),6.78(1 H,
d, J=7.1Hz),7.02(1H,t,J=7.7Hz),7.14(1 H,d,J=7.3Hz).
Fraction 2 (more polar compound)
15 1 H-NMR(CDCI 3 )8:0.02(6H,s),0.74(9H,s), 1.60-1. 70(1 H,m),2. 15-2. 23(1 H,m),2.42-2.50(2H,m), 3. 68(2H,brs),

3.95-4.02(2H,m), 4.36(1 H,dd,J=1 0Hz,5.2Hz),4. 63(1 H,dd,J=1 2Hz,5.5Hz), 6. 80(1 H,d ,J=7.0Hz),7.20-7.24(2H,m).

(5) According to the procedure described in the working example No.1 , the polar compound (2.40 g, 7.23 mmol)
from the fraction 2 obtained above in (4) was used to afford a yellow solid compound (2.71 g).

(6) The compound (2.71 g, 6.00 mmol) obtained above in (5) was suspended to the methanol-tetrahydrofuran(1 :
20 1 ,200ml).To the mixture was added 2N hydrochloric acid (10 ml) at room temperature and the reaction mixture

was stirred for 6 hours at the same temperature. The reaction mixture was concentrated to afford a residue, which
was dehydrated by heating with toluene twice to remove water. The crude compound obtained was recrystallized
from hexane-ethylacetate-tetrahydro furan to afford the titled compound (1 .85 g).

1 H-NMR(DMSO-d 6 )S:1 .27-1 .40(1 H,m),1 .72-1 .78(1 H,m),2.20-2. 27(1 H,m),2. 40-2.50(1 H,m),2. 53-2. 62 (1 H,m),3.59
25 (1H,t,J= 7.5Hz),3. 85-3. 93(1 H, m), 4.90(1 H,dd,J=8.0Hz,5.5Hz),5.97 (1 H,br), 7. 1 7-7.22(1 H,m), 7.33(1 H ; d,J=8.0Hz),

7.40 (1 H,d, J=9.0Hz),7-47(1 H,t,J=7.5Hz),7.98(1 H,t,J=8.0Hz),8.1 8(1 H,d,J= 7.0Hz),8.30(1 H,d,J=4.0Hz),1 0.6(1 H,
br),11.0(1H,br).
mass:339(M-i-1) + .

30 Working Example No.123

[0495]

(1) According to the procedure described in the working example No. 122(2), the compound (4.50 g, 13.4 mmol)
35 obtained from the working example No. 131 (1) was used to afford a yellow solid compound (3.94 g).

(2) According to the procedure described in the working example No. 122(3) and (4), the compound (3.94 g, 8.47
mmol) obtained above in (1) was used to afford fraction 1 (less polar compound, 238 mg) and fraction 2 (more
polar compound, 1.14 g).

Fraction 1(less polar compound):
40 1 H-NMR(CDCl3-CD 3 OD)8:0.08(3H,s),0.11(3H,s),0.93(9H : s),1.51 (3H,d,J=6.2Hz), 3.84(2H,br), 5.26(1 H,m), 5.96

(1 H,d, J=3.3Hz), 6.10(1 H, dd, J=3.1 Hz, 1 .0Hz), 6.78(1 H, d, J=8.0Hz), 7.01 (1 H, t, J=7.7H z), 7.13(1 H, d, J=7.3Hz).
Fraction 2(more polar compound):

1 H-NMR(CDCI 3 )5:0.07(3H,s), 0.11(3H.s), 0.85-0.95(1 H,m) ; 0.92 (9H,s), 1 .24-1 .35(2H,m), 1 .52(3H ; d,J=6.3Hz),
1.52-1.55 (1H,m), 5.27(1 H,q), 6.28(1 H,d,J=3.4Hz), 7.07(1 H,d,J=3.6Hz), 7.31(1H,dd ,J=8.5Hz, 7.3Hz), 7.92(1 H,
45 dd, J=7.3Hz, 1 .0Hz), 8.28(1 H,dd, J=8.5H

z,1.0Hz).

(3) According to the procedure described in the working example No.1 , the polar compound (300 mg, 0.87 mmol)
from the fraction 2 obtained above in (2) was used to afford a yellow solid compound (389 mg).

(4) According to the procedure described in the reference example No. 7, the compound (200 mg, 0.429 mmol)
50 obtained above in (3) was used to afford the titled compound (92 mg).

1 H-NMR(DMSO-d 6 )5:0. 80-0.95(1 H,m),1 .1 4(3H,d,J=6.3Hz),1 . 17-1. 28(1 H,m),2.25-2.40(2H,m),3.70-3.74(1 H,m),
3.80-3.90 (1H,m), 4.78-4.85(2H,m), 7.06(1 H,dd,J=7.2Hz ; 5.0Hz), 7.33 (2H,t,J=7.4Hz), 7.46(1 H,t,J=7.9Hz),
7.76-7.82(1 H,m), 8.26-8. 30(2H,m),9. 90(1 H,s), 11 .0(1 H,br).

55 Working Example No.1 24

[0496] The more polar compound (1 4 mg) obtained from the fraction 2 of the working example No.1 28(5) was dis-
solved in methanol-tetrahydrofuran (1:1, 2 ml). To the solution was added 1 N hydrochloric acid (1 .0 ml) at room tem-

161

EP 1 199 306 A1

perature and the reaction mixture was stirred for 30 minutes at the same temperature. The reaction mixture was neu-
tralized with saturated aqueous sodium hydrogencarbonate and then extracted with chloroform. After being dried over
magnesium sulfate, the mixture was filtered. The filtrate was concentrated to afford a residue, which was purified by
thin layer chromatography (ethyl acetate-methanol, 30: 1 ) to provide the titled compound (4. 1 mg) as well as the com-
5 pound (3.8 mg) of the working example No. 127.

1 H-NMR(DMSO-d 6 )5:0. 92-1 .09(1 H,m),1 .1 8(2H ; d,J=6.6Hz),1 .60-1 .74(1 H,br),2. 68-2. 76(1 H,m),2. 80-3.00(1 H,m), 3. 28
(1H,dd, J=11Hz,9.0Hz),3.63(1H,dd,J=11Hz,8.5Hz),4.87(1H,dd ) J=11Hz,5. 2Hz),6.97(1 H,d,J=4.6Hz),6.99-7.05(1 H,m),
7.45-7.60(2H,m), 7.68-7.76(1 H,m),8,1 9-8.23(1 H,m),8. 32(1 H,dd,J=7.7Hz,1 .3Hz) ; 8.94(1 H,br),1 2.00(1 H,br).
mass:323(M+1)+.

10

Working Example No.125
[0497]

*s (1 ) The compound (1 2.3 g, 38.2 mmol) of the working example No. 1 28(1 ) was dissolved in tetrahydrofuran (1 50

ml). The mixture was cooled to -78 °C. A solution (46.0 ml) of diisobutylaluminum hydride in toluene (1 .0 M, 46.0
mmol) was added at the same temperature. The reaction mixture was stirred for 15 minutes and saturated aqueous
ammonium chloride (25 ml) was added at the same temperature. The whole was warmed up to room temperature.
To the reaction mixture was added magnesium sulfate and the whole was filtered. The filtrate was concentrated

20 to afford a residue, which was dissolved in chloroform (150 ml), and imidazole (5.20 g, 81 .1 mmol) and chlorotri-

isopropylsilane (9.40 g, 43.9 mmol) were added. The reaction vessel was filled with nitorogen. The whole was
stirred for 12 hours at room temperature. The reaction mixture was diluted with ethyl acetate and washed with
water and brine respectively and then dried over magnesium sulfate. After filtration, the filtrate was concentrated
to afford a residue, which was purified by column chromatography on silica gel. Elution with hexane-ethyl acetate

25 (1 0:1 ) provided a yellow solid compound (1 7.2 g).

(2) The compound (17.2 g, 15.6 mmol) obtained above in (1) was subjected to the reaction described in the ref-
erence example No. 2(2) to afford a yellow solid compound (4.9 g).

(3) The compound (4.90, 12.2 mmol) obtained above in (2) was dissolved in tetrahydrofuran (70 ml). To the solution
was added 6N hydrochloric acid (20 ml) at room temperature. The reaction mixture was stirred for 1 hour at the

30 same temperature. The reaction mixture was alkalized by adding 1 N sodium hydroxide. The whole was extracted

with ethyl acetate and the organic layer was dried over magnesium sulfate. After filtration, the filtrate was concen-
trated to afford a crystal, which was washed with hexane-ethyl acetate and dried. A yellow solid compound (2.94
g) was obtained.

(4) The compound (1 80 mg, 0.73 mmol) obtained above in (3) was dissolved in methanol (5.0 ml) and tetrahydro-
35 furan (1 6 ml). To the solution was added triethylamine (0.20 ml) and 1 0% paradium carbon catalyst (1 00 mg). The

whole was stirred for 1 hour at 50°C under an atomosphere of hydrogen. The reaction mixture was filtered by celite
and the filtrate was concentrated to afford a colorless solid compound (1 63 mg).

(5) According to the procedure described in the working example No.1 , the compound (163 mg, 0.75 mmol) ob-
tained above in (4) and 2-pyridinecarbonylazide (1 07 mg, 0.72 mmol) were used to afford the titled compound (7

40 mg).

1 H-NMR(DMSO-d 6 )5:1 .03-1 .1 0(1 H,m),3.02-3.21 (1 H,m),3.30-3.65 (4H,m),3. 87-3. 89(1 H,m), 4. 95-5. 02(1 H,m),

7.06-8.45(7H,m), 9.02(1 H,br),1 1 .9(1 H,br).

mass:339(M+1)+.

45 Working Example No.126

[0498]

(1) To a solution of the compound (85 mg, 0.251 mmol) of the working example No. 125 and triphenylphosphine
50 (132 mg, 0.503 mmol) in tetrahydrofuran (6 ml) were added diphenylphosphorylazide (0.140 ml, 0.650 mmol) and

a 40% solution (0.220 ml, 0.505 mmol) of diethylazodicarbolxylate at room temperature. The reaction mixture was
stirred for 1 hour at the same temperature and diluted with ethyl acetate. The mixture was washed with water and
brine respectively. The organic layer was dried over magnesium sulfate. After filtration, the filtrate was concentrated
to afford a residue, which was purified by thin layer column chromatography eluted with chloroform-methanol (1 0:
55 1 ). Ether was added to the crude compound to afford a crystal (24 mg).

(2) The compound (24 mg) obtained above in (1) was dissolve in methanol-tetrahydrofuran (1:1, 2 ml). To the
solution was added 10% paradium carbon catalyst (10 mg ) at room temperature. The reaction vissel was filled
with hydrogen. The mixture was stirred at room temperature under an atomosphere of hydrogen until the disap-

162

EP 1 199 306 A1

pearance of the starting material. The reaction mixture was filtered by celite. The filtrate was concentrated to afford
a residue. To the residue, was added ether to afford the crystal. The crystal was collected by filtration, washed
with ethyl acetate and chloroform, and then dried to afford the tilted compound (4.6 mg).

1 H-NMR(DMSO-d 6 )S:0.97-1 .1 0(1 H,m), 2.72-2.82(1 H,m),2.87-3.00 (2H,m),3.1 0-3.20(1 H ! m),3.30-3.60(2H,m) !
5 4.96-5.01 (1 H,m) 7.03-7.1 4(1 H,m),7.31 -7.34(1 H, m), 7.40-7. 50(2H,m), 7. 77-7. 83 (1 Km), 8.1 6(2H,br),8.26(1 H,d,

J=8.1 Hz), 8.37(1 H,d,J=4.0Hz),1 0 .1(1 H,s),11 .2(1 H,br).
mass : 338 (M+1) +

Working Example No.127

10

[0499] According to the procedure described in the working example No. 124, the titled compound was obtained.
1 H-NMR(DMSO-d 6 )5:0.45(2H,d,J=7.0Hz), 1.55-1. 70(1 H,br), 2. 08-2.1 9(1 H,m),2.48-2. 68(1 H,m),2. 88-3.02(1 H,m),
3.41-3.53 (1 H,m),3.66-3.80(1 H,m),4.96(1 H,d,J=5.3Hz),6.92(1 H,d, J=8.3Hz),6. 99-7. 05(1 H,m),7.46-7.60(2H,m),
7.72-7.77(1 H,m), 8.20 -8.23(1 H,m), 8. 32-8.37(1 H,m), 8. 66(1 H,br), 12. 00(1 H,br).
15 mass:323(M+1)+.

Working Example No.128

[0500]

20

(1) According to the procedure described in the reference example No.2(1), pyrrole-3-carboxyaldehyde was used
to afford the titled compound.

(2) According to the procedure described in the working example No. 1 22(2), the compound (139 mg, 0.433 mmol)
obtained above in (1) was used to afford the titled compound.

25 (3) According to the procedure described in the reference example No. 2(2), the compound obtained above in (2)

was used to afford the titled compound as a mixture of isomers in a ratio of 2 to 1 .

(4) According to the procedure described in the working example No. 122(4), the compound obtained above in (3)
was used to afford a mixture, which was used for the next reaction without further purification.

(5) The mixture (22 mg) obtained above in (4) and 2-pyridinecarbonylazide (26 mg, 0.17 mmol) were subjected in
30 the similar manner to that described in the working example No.1 . The reaction mixture was concentrated to afford

a residue, which was purified by thin layer chromatography eluted with hexane-ethyl acetate (1 :2) to afford fraction
1 (less polar compound) and fraction 2 (more polar compound).

(6) The fraction 1 (less polar compound, 11 mg) obtained above in (5) was dissolved in methanol-tetrahydrofuran
(1 :5, 1 .2 ml). To the solution was added 1 N hydrochloric acid (1 .0 ml). The reaction mixture was stirred at the same

35 temperature and concentrated to afford a residue. The residue was diluted with ethyl acetate and washed with

saturated sodium hydrogencarbonate and brine respectively. The organic layer was dried over magnesium sulfate.
After filtration, the filtrate was concentrated to afford a residue, which was purified by thin layer chromatography
eluted with chloroform-methanol (10:1) to provide the titled compound (3.1 mg).

1 H-NMR(acetone-d 6 )5:1 .29(1 H,br),2.52-2.61 (2H,m), 3. 00-3.1 0 (2H,m),3. 29-3.41 (1 H,m), 3.54-3. 70(2H,m),5. 08
40 (1H,d,J=5.4Hz), 7.05-7.12(1 H, m), 7.23(1 H,d,J=8.4Hz), 7.32-7. 36(1 H,m), 7.45 (1 H,t,J=7.7Hz),7.78-7.87(1 H,m),

8.36-8.42(2H,m),8.96(1 H, br),1 1 .9(1 H,br).

Working Example No.129

45 [0501]

(1) To a solution of the compound (1 00 mg, 0.467 mmol) obtained from the reference example No. 2(2) in methanol
(15 ml) was added iron powder (200 mg, 3.58 mmol) and 6N hydrochloric acid (0.500 ml, 3.00 mmol). The reaction
mixture was stirred for 30 minutes at room temperature and diluted with ethyl acetate (200 ml). The whole was

50 washed with saturated aqueous sodium hydrogencarbonate (100 ml), water and brine respectively. The organic

layer was dried over magnesium sulfate. After filtration, the filtrate was concentrated to afford a residue, which
was purified by column chromatography on silica gel (wakogel C-300). Elution with hexane-ethyl acetate (5:1)
afforded a light green solid (71 mg).

(2) According to the procedure described in the working example No.1 , the compound (50 mg) obtained above in
55 (1) was used to afford the titled compound (65 mg).

1 H-NMR(DMSO-d 6 )5:6.34(1H,t,J=3.1Hz),6.65(1H,d,J=3.1Hz) ! 7.08(1 H,dd,J=6.7Hz,5.6Hz),7.24-7.29(3H,m), 7.38
(1 H,d, J=7.3Hz),7.77-7.83(1 H,m),8.27(1 H,d,J=8.2Hz),8.31 (1 H,dd, J=5.1 Hz,1 .1 Hz),1 0.1 (1 H,brs),1 1 .0(1 H ; br).

163

EP 1 199 306 A1

Working Example No.130

[0502] According to the procedure described in the working example No. 122(5) and (6), the fraction 1 (less polar
compound, 300 mg, 0.91 mmol) obtained from the working example 122(4) was used to afford the titled compound
5 (216 mg).

1 H-NMR(DMSO-d 6 )5:4.60(2H,s), 5.65(1 H,br), 6.20(1 H,s), 6.68 (1 H,s), 7.1 4-7.20(1 him), 7.25(1 H,t,J=7.4Hz),
7.35-7.43(2H, m), 7.94(1 H,t, J=6.9Hz), 8.20(1 H,d,J=7.4Hz), 8.34(1 H,d,J=5.5Hz) , 1 0.8(2H,br).

Working Example No.131

10

[0503]

(1) According to the procedure described in the reference example No. 2(1), 2-bromo-3-nitrobenzonic acid (10.0
g, 40.7 mmol) and 2-acetylpyrrole (8.90 g, 81 .6 mmol) were used to afford a yellow solid (9.20 g).
*s (2) According to the procedure described in the reference example No.2(2), the compound (2.00 g, 5.93 mmol)

obtained above in (1) was used to afford a light green solid (941 mg).

(3) According to the procedure described in the working example No. 129, the compound (300 mg, 1.17 mmol)
obtained above in (2) was used to afford the titled compound (277 mg).

1 H-NMR(DMSO-d 6 )S:6. 32-6.35(1 H,m),6.74(1 H,s),7.07(1 H,dd, J=7.2Hz,5.2Hz),7.1 9(1 H,s), 7.26(1 H,s),7.40(1 H,t,
20 J=8.0Hz),7.4 7(1H,d,J=8.6Hz),7.66(1H,dd,J=7.9Hz,1 .5Hz), 7. 78-7.83(1 H,m), 8.25(1 H,dd, J=5.2Hz,1 .6Hz),8.47

(1H,dd,J=8.0Hz,1.6Hz),10.1(1H ,s),1 0.8(1 H,brs),1 2.0(1 H : s).
mass:347(M+1) + .

Working Example No.132

25

[0504]

(1) According to the procedure described in the working example No. 122(2), the compound (4.5 g, 13.4 mmol)
obtained from the working example No.131 (1) was used to afford the titled compound (3.94 g).
30 (2) According to the procedures described in the working example No.1 22(3) and (4), the compound (3.94 g, 8.47

mmol) obtained above in (1 ) was used to afford the fraction 1 (less polar compound, 238 mg) and the fraction 2
(more polar compound, 1.14g).

(3) According to the procedure described in the working example No.1 , the fraction 1 (less polar compound, 200
mg, 0.58 mmol) obtained above in (2) was used to afford a crystal (247 mg).
35 (4) According to the procedure described in the reference example No. 7, the compound (247 mg, 0.53 mmol)

obtained above in (3) was used to afford the titled compound (85 mg).

1 H-NMR(DMSO-d 6 )8:1 .58(3H,d,J=7Hz),5.02(1 H,q,J=7Hz), 6.07(1 H,d,J=3Hz),6.55(1 H,d,J=3Hz),6.96(1 H,brd,
J=8Hz),7.06(1 H,t,J=5Hz),7.22(1 H,t,J=7Hz),7.43(1 H,d,J=7Hz), 7. 69-7.75 (1 H,m), 8.23-8. 27(2H,m).

40 Working Example No.1 33

[0505]

(1) To a solution of the compound (16 mg) of the working example No. 299(1) in ethanol (0.2 ml) were added
45 1 -butanethiol (4.2 uJ) and sodium ethoxide (2.6 mg). The reaction mixture was stirred for 15 hours at room tem-
perature and concentrated. The residue was purified by TLC (Merck A rt5 744) eluted with hexane-ethyl acetate (1 :
5) to afford the titled compound (8 mg).

(2) To a solution of the compound (8 mg) obtained above in (1 ) in tetrehydrofuran (2 ml) was added 1 N hydrochloric
acid (1 ml). The mixture was stirred for 15 minutes at room temperature. The reaction mixture was concentrated

50 to afford a residue, which was crystallized from ether-methanolto afford the titled compound (4 mg) as a white solid.

1 H-NMR(DMSO-d 6 )

0.87(3H,t,J=7.2Hz),1 .07-1 .24(1 H,m),1 .28-1 .40(2H,m), 1 .49 (2H,tt,J=7.3 ; 7.7Hz),2.25-2.58(5H,m),2.71 -2.88(4H,
m), 3. 27-3.34(1 H,m),3.38-3. 82(1 H,m),4.82(1H,dd,J=5.4, 11 Hz), 7.03 (1 H,d, J=5.4Hz), 7.1 7(1 H^), 7.32(1 H,d,
J=7.5Hz), 7.47(1 H,t,J=7. 8Hz), 8.22(1 H,d, J=5.4Hz), 8.28(1 H,d,J=8.4Hz), 10.1(1H,br), 11.1 (1H,br).
55 mass:425(M+1)+.

164

EP 1 199 306 A1

Working Example No.134
[0506]

5 (1) According to the procedure described in the working example No. 289(6), the compound of the reference ex-

ample No. 8 was used to afford the titled compound.

(2) A solution of the compound (1 9 mg) obtained above in (1), isopropanol (15 and triphenylphosphine (50 mg)
in tetrahydrofuran (0.2 ml) were cooled to 0 °C. To the mixture was added diethyl azodicarboxylate (82 \x\). The
reaction mixturewas stirredfor30 minutes at room temperature and diluted with chloroform. The whole was washed

10 with water and brine and dried over magnesium sulfate. After filtration, the filtrate was concentrated to afford a

residue, which was purified by TLC (Merck Art5744) eluted with chloroform-methanol (20:1) to afford the titled
compound (1 8 mg).

(3) The compound (18 mg) obtained above in (2) was subjected to the similar reaction to that described in the
reference example No. 11 to afford the compound, which was further subjected to the reaction described in the

*s working example No. 133(2) to afford a hydrochloride of the titled compound (5 mg) as a white solid.

1 H-NMR(DMSO-d 6 )

1 .06-1.20(1 H,m),1.24(6H,sx2),2.25-2.44(3H,m),2. 93-2. 99 (2H,m),3.11 -3.1 6(2H,m),3.21 -3.36(2H,m) ; 3.49-3.59
(1H,m), 4.80-4.86(1 H, m),7.04-7. 06(1 H,m), 7. 26-7. 33(2H,m), 7. 46 (1 H,t,J=7.8Hz),8.26-8.29(2H,m),8.78(2H,br),
10. 2(11-1, s), 1 0.9(1 H,br).
20 mass:394(M+1)+.

Working Examples No.1 35-136

[0507] According to the procedure described in the working example No.134, the compounds of the working examples
25 No.1 35 and No. 136 were prepared.
mass:420(M+1)+.

Working Example No.1 36

30 [0508] mass:434(M+1)+

Working Example No.1 37

[0509]

35

(1 ) According to the procedure described in the working example No. 84(2), the compound of the reference example
No. 8 and tert-butyldiphenylsilylether of salicylaldehyde were used to afford the titled compound.

(2) According to the procedure described in the working example No. 133(2), the compound obtaine above in (1)
was used to afford the titled compound (3 mg) as a white solid. mass:696 (M+1) + .

40

Working Example No.1 38
[0510]

45 (1) The compound of the working example No. 137 (1) was subjected to the reaction described in the reference

example No. 7 to afford the titled compound.

(2) The compound obtained above in (1) was subjected to the reaction described in the working example No.1 33

(2) to afford the hydrochloride of the titled compound (4 mg) as a white solid.

1 H-NMR(DMSO-d 6 )

50 1 .06-1 .24(1 H,m), 2.25-2.48(2H ! m), 2.49-2.63(1 H,m),2.98-3.03 (2H,m), 3.1 3-3.27(2H,m), 3.27-3.35(1 H,m),

3.45-3.79(1 H,m), 4.11 -4,1 4(2H,m), 4.80-4.85(1 H,m), 6.83-7.01 (3H,m), 7.22-7.38 (3H,m),7.44-7.49(1 H,m),
8.25-8.29(2H,m),8.90(2H,br), 10.1 (1H,br), 1 0.2(1 H,br), 11.0(1H,br).
mass:458(M+1) + .

165

EP 1 199 306 A1

Working Example No.139
[0511]

5 (1) A mixture of the compound (29 mg) of the working example No. 137(1), d ite rt- b uty I di carbon ate (1 6 mg), triethyl-

amine (15 uJ) and chloroform (0.2 ml) was stirred for 3 hours at room temperature. The reaction mixture was
concentrated to afford a residue, which was purified by TLC (Merck Art5744) eluted with chloroform-methanol (20:
1) to afford the titled compound (32 mg).

(2) According to the procedure described in the reference example No. 7, the compound (35 mg) obtained above
10 in (1) was used to afford the titled compound (24 mg).

(3) According to the procedure described in the working example No. 134(2), the compound (24 mg) obtained
above in (2) and 1-butanol (5 \x\) were used to afford the titled compound (3 mg).

(4) The compound (8 mg) obtained above in (3) was subjected to the reaction procedure described in the working
example No. 133(2) to afford the hydrochloride of the titled compound (3 mg).

15 1 H-NMR(DMSO-d 6 )

0. 91 (3H,t,J=7.5Hz), 1.06-1. 24(1 H,m),1.43(2H,tt,J=6. 6, 7.5Hz), 1 .73(2H ; tt,J=6.6,6.6Hz), 2.25-2. 59(3H,m), 2.98?
3.05 (2H,m), 3.1 4-3. 24(2H,m),3.27-3. 35(1 H, m),3. 43-3. 65(1 H,m), 4.03(2H,t,J=6.6Hz), 4. 1 5(2H,brt,J=5.4Hz),
4.79-4.86(1 H,m), 6.97-7.1 0(3H,m), 7.27-7. 49(5H,m), 8.25-8.29(2H ,m),9.01 (1H,br), 1 0. 1 (1 H,br), 1 0.9(1 H,br).
mass : 514 (M+1)+.

20

Working Example No.140
[0512]

25 (1) According to the procedure described in the working example No. 84(2), the compound (30 mg) of the reference

example No. 8 and o-anisaldehyde (9 uJ) were used to afford the monoalkyl compound (A) (16 mg) and dialkyl
compound (B) (11 mg).

(2) According to the procedure described in the working example No.133(2) ; the compound (A) (16 mg) obtained
above in (1 ) was used to afford the hydrochloride of the titled compound (1 2 mg) as a light yellow solid.
30 1 H-NMR(DMSO-d 6 )

1.05-1.12(1H,m),2.26-2.61(3H,m),2.99-3.05(2H,m),3.14-3.21 (2H, m),3. 22-3.35(1 H,m),3. 49-3. 84(1 H,m), 3. 85(3H,
s),4.13-4.17 (2H,m),4.81 -4.86(1 H, m), 6. 98-7.03(2H,m), 7.1 0(1 H ,d,J=4.8Hz), 7.27-7.34(2H,m),7.40-7.49(3H,m),
8.26-8.29(2H,m),9.01 (2H,br),1 0.3(1 H,br),1 0.9(1 H,br).
mass:472(M+1)+.

35

Working Example No.141

[0513] The compound (B) (7 mg) obtaine from the working example No. 140(1) was subjected to the reaction de-
scribed in the working example No. 133(2) to afford the hydrochloride of thetitled compound (4 mg) as a lightyellowsolid.
40 iH-NMR(DMSO-d 6 )

1 .03-1 .1 0(1 H,m), 2. 26-2. 81 (3H ; m),3.1 6-3.40(4H,m),3.70 (3H,s),3.75(3H,s),3.43-3.99(2H,m),4.29-4.46(4H,m),4.81 -
4.86(1 H, m), 6. 90-7. 13(5H,m), 7. 27-7.35(2H,m), 7. 42-7.51 (5H, m), 8.22-8. 28(2H ; m), 8. 93(1 H,br),1 0.3(1 H,br),1 0.8(1 H,
br).

mass:592(M+1)+.

45

Working Example No.142
[0514]

50 (1) The compound (30 mg) of the working example No. 164(3) was dissolved in acetonitrile-methylenedichloride

(3:1 , 0.4ml). The reaction vessel was filled with nitrogen. To the solution were added (Boc) 2 0 (0.12ml), nitroethane
(25 fil) and 4-dimethylaminopyridine (4 mg). The reaction mixture was stirred for 1 hour at room temperature. To
the reaction mixture was added water and the whole was extracted with chloroform. The organic layer was washed
with water and brine and dried over magnesium sulfate. After filtration, the filtrate was concentrated to afford a

55 residue, which was purified by TLC (Merck a rt5 744) eluted with chloroform-methanol (30:1) to afford the adducts

(32 mg). The diastereomer adducts were resolved by HPLC [CHIRALPAK AD, Dicel Chem.lnd.Co., 0.46 x 25cm,
hexane-ethanol (20:80), 1 .0 ml/min] to afford the fraction (A) (12 mg) at Rt=9.64 min and the fraction (B) (13 mg)
at Rt=14.58 min.

166

EP 1 199 306 A1

(2) According to the procedure described in working example No. 133(2), the compound of the working example
No. 142 was prepared from the (1)-A as a light yellow powder and the compound of the working example No. 143
was prepared from the (1 )-B as a light yellow powder.
MASS:392(M+1)+.

5

Working Example No.143

[0515] The compound of the working example No.143 was obtained from the diastermer of the working example No.
142.

10 mass:392(M+1)+.

Working Examples No.1 44-147

[0516] According the procedure described in the working example No.142 ; the compounds of working examples
15 from No. 1 44 to No. 1 47 were prepared.

Working Example No.144

[0517] 1 H-NMR(CDCI 3 )

20 1.18(3H,t,J=7.5Hz),1.16-1.44(1H,m),2.40(2H,q,J=7.5Hz), 2.36-2.44(2H ,m),2.57-2.65(1 H,m),2.87(1 H,dd,J=7.2,17Hz),
3.42-3.53(2H,m),3.73-3.82(1 H,m),4.80(1 H,dd,J=5.7,1 1 Hz), 5.54(1 H,dd,J=7.2,1 1 Hz), 6. 97(1 H,d,J=9.0Hz),6.98(1 H,br),
7.56-7.57(2H ) m) ) 8.20(1H,d,J=5.1Hz) ) 8.37(1H,d,J=7.2Hz),9.05(1H,br),11.9(1H ! br).
mass:406(M+1)+.

25 Working Example No.145

[0518] mass:406(M+1) + .

Working Example No.146

30

[0519] mass:406(M+1)+.
Working Example No.147
35 [0520] mass:406(M+1)+

Working Examples No.1 48-151

[0521] According to the procedure described in the working example No. 142, the compounds of the working examples
40 from No. 148 to No. 151 were prepared as a mixture of diasteomer.

Working Example No.1 48

[0522] mass:420(M+1 )+.

45

Working Example No.1 49
[0523] mass:420(M+1 )+.
50 Working Example No.1 50
[0524] mass:448(M+1 )+.
Working Example No.1 51

55

[0525] mass:448(M+1)+.

167

EP 1 199 306 A1

Working Examples No.1 52-155

[0526] According to the procedure described in the working example No. 156, the compounds of the working examples
from No. 152 to No. 155 were prepared as a single isomer.

5

Working Example No.152
[0527] mass:434(M+1 )+.
fo Working Example No.153
[0528] mass:434(M+1 )+.
Working Example No.154

15

[0529] mass:434(M+1)+.
Working Example No.155
20 [0530] mass:434 (M+1) + .
Working Example No.156
[0531]

25

(1) A mixture of the compound (30 mg) obtained from the working example No. 1 64(3), 1 -pyrroline-N-oxide (59 mg)
and chloroform (2 ml) was stirred for 23 hours at 80 °C. The reaction mixture was cooled to room temperature and
then extracted with chloroform. The organic layer was washed with water and brine and dried over magnesium
sulfate. After filtration, the filtrate was concentrated to afford a residue, which was purified by TLC (Merck Art5744)

30 eluted with chloroform-methanol (20:1 ) to afford a light yellow oily compound (24 mg).

(2) Accroding to the procedure described in the working example No.1 33(2), the compound (6 mg) obtained above
in (1) was used to afford the tilted compound (5 mg).

1 H-NMR(CDCI 3 )

1 .22-1 .35(1 H,m),1 .58-1 .86(3H,m),1 .99-2.1 7(2H,m),2.35-2.62(4H ,m),3. 13-3.22(1 H,m),3.33-3.49(2H,m),
35 3.72-3.84 (2H,m),4.79(1 H,dd,J=5.7,1 1 Hz),5.08(1 H,t,J=7.2Hz),6.95-7.01 (2H,m),7.47(1 H,t,J=7. 5Hz), 7.54(1 H,d,

J=6.3Hz), 8.09(1 H,s) ,8.16(1 H,d,J=5.1 Hz), 8.32(1 H,d,J=6.6Hz),1 1 .9(1 H,s).
mass:420(M+1) + .

Working Example No.1 57

40

[0532] According to the procedure described in the working example No.1 56, the optical isomer obtained form the

working example No.1 64(3) was used to afford the titled compound.

mass:420(M+1)+.

45 Working Example No.1 58

[0533]

(1) According to the procedure described in the working example No.1 42, the compound (30 mg) obtained from
50 the working example No.1 64(3) and 2-(2-nitroethoxide)tetrahydropyran (53 jxl) were used to afford the titled com-
pound (39 mg).

(2) According to the procedure described in the working example No.1 33(2), the compound (7 mg) obtained above
in (1) was used to afford the titled compound (4 mg) as a light yellow solid.

1 H-NMR(CDCI 3 )

55 1.22-1.39(1H,m),2.35-2.62(3H,m),3.04(1H,dd,J=6.9,17Hz), 3.42-3.82(3H,m),4.47(1 H,d,J=1 4Hz),4.54(1 H,d,

J=14Hz), 4.79(1 H,dd,J=5. 7, 10Hz),5. 66-5. 73(1 H, m), 6. 85-6. 88(1 Km), 6. 99(1 H,s), 7.22-7. 26(1 H,m), 7.48 (1H,t,
J=7.8Hz), 7.54(1 H,d,J=7.5Hz),8.1 9(1 H,d, J=5.4Hz),8. 25-8.30(1 H,m), 9.16(1 H,br),11 .9(1 H,s).
mass:408(M+1)+.

168

EP 1 199 306 A1

Working Example No.159

[0534] According to the procedure described in the working example No. 1 58, the optical isomer obtained from the
working example No. 1 64(3) was used to afford the titled compound
5 mass:408(M+1)+.

Working Example No.1 60

[0535] According to the procedure described in the working example No. 156, the titled compound of the working
10 example No. 160 was prepared as a mixture of diastereomer.
mass:478(M+1)+.

Working Example No.1 61

*s [0536] According to the procedure described in the working example No.1 57, the titled compound of the working
example No.1 61 was prepared as a mixture of diastereomer.
mass:478(M+1)+.

Working Example No.1 62

20

[0537] The compound of the working example No.1 64(2)-B was subjected to the reactions described in the working
examples No.1 64(3) to (5) afford the compound (7 mg) of the working example No.1 62 as a light yellow amorphous
compound and the compound (9 mg) of the working example No.1 63 as a light yellow amorphous compound.
mass:468(M+1)+.

25

Working Example No.1 63

[0538] The compound of the working example No.1 63 was obtained as a diasteromer of the working example No.1 62.
mass:468(M+1)+.

30

Working Example No.1 64
[0539]

35 (1) The compound (3.08 g) of the reference example No. 6 was subjected to the optical resolution by HPLC [CHI-

RALCEL OD (Diecel Chem. Indus. Ltd., 0.46 x 25 cm, hexane-isopropanol (60:40), 0.4ml/min] to afford thefraction
(A) (1 .37 g) at Rt=14.54 min and the fraction (B) (1 .21 g) at Rt=25.58 min.

(2) (1)-(A) (15.6 g) and (1)-(B) (15.9 g) were subjected to the reaction described in the reference example No. 7 to
afford (2)-(A) (11 .0 g) as a colorless amorphous compound and (2)-(B) (10.9 g) as a colorless amorphous com-

40 pound.

(3) Accroding to the procedure described in the working example No. 299(1), the compound (727 mg) of (2)-(A)
was used to afford an amorphous compound (606 mg).

(4) According to the procedure described in the working example No. 300(1), the compound (606 mg) obtained
above in (3) was used to afford the titled compund (712 mg). The compound was subjected to the optical resolution

45 by HPLC (CHIRALCEL OD Diecel Chem. Indus. Ltd., 0.46 x 25 cm, ethnaol, 0.5 ml/min) to afford the fraction (A)

(360 mg) at Rt=22.58 min and the fraction (B) (329 mg) at Rt=38.84 min.

(5) (4)-(A) and (4)-(B) were subjected to the reaction described in the working example No. 133(2) respectively.
The compound (291 mg) of the working example No.1 64 was prepared from (4)-(A) as a light yellow amorphous
compound, and the compound (235 mg) of the working example No. 165 was prepared from (4)-(B) as a light yellow

50 amorphous compound.

mass:468(M+1) + .

Working Example No.1 65

55 [0540] The compound of the working example No.1 65 was obtained as a diasteromer of the working example No.1 64.
1 H-NMR(CDCI 3 )

1 .24-1 .31 (1 H,m),1 .82-1 .99(1 H ; m), 2.30-2. 45(3H,m),2.58-2.74(3H,m),2. 82(1 H,dt, J=5.4,9Hz),2.90(1 H,t,J=8.7Hz),
3.29-3.34(1 H, m), 3. 41 -3.50(1 him), 3. 62-3. 81 (3H, m), 6.79(1 H,dd, J=6, 11 Hz), 6. 80(1 H,s), 6. 95(1 H,d,J=5.1 Hz), 7.23-7.36

169

EP 1 199 306 A1

(5H,m), 7.45(1 H,t,J=7.2Hz),7.53(1 H,d,J=7.5Hz),8.09(1 H,d,J=5.4Hz),8. 25(1 H,s),8.33(1 H,d,J=9Hz),1 2.0(1 H,s).
mass:468(M+1)+.

Working Examples No.166-169

5

[0541] According to the procedure described in the working example No.1 83, the compounds of the working examples
from No. 1 66 to No. 1 69 were prepared

Working Example No.1 66

10

[0542] mass:392(M+1)+.
Working Example No.1 67
15 [0543] mass:392(M+1)+
Working Example No.1 68
[0544] mass:392(M+1 )+.

20

Working Example No.1 69

[0545] mass:392(M+1 )+.

25 Working Example No.1 70

[0546] According to the procedure described in the working example No.1 71 , the compound of the working example

No.1 62 was used to afford the titled compound.

mass:478(M+1)+.

30

Working Example No.1 71

[0547] A mixture of the compound (291 mg) of the working example No.1 64, (Boc) 2 0 (2.86 ml), 20% palladium
hydroxide carbon catalyst (1 50 mg), ethyl acetate (30 ml) and methanol (5 ml) was stirred for 1 5.5 hours at 60 °C under
35 an atomosphere of hydrogen. The reaction was filtrated by celite and the filtrate was concentrated to afford a residue,
which was purified by column chromatography on silica gel (Wakogel C-300) eluted with hexane-ethyl acetate (1 :1 -1 :
5) to afford the titled compound (1 83 mg) as a colorless amorphous compound.
1 H-NMR(CDCI 3 )

1 .22-1.44(1 H,m),1.49(9H,s),1 .96-2.04(1 H,m), 2.27-2. 47 (3H,m),2.58-2.64(1 H,m),3.30-3.34(2H,m),3.41 -3.49 (2H,m),
40 3. 57-3. 89(3H,m), 4.79(1 H,dd,J=5.7,1 1 Hz), 6. 81 (1 H,s) ; 6.88(1 H,d,J=5.4Hz),7.46-7.57(2H,m),8.1 5(1 H,d, J=5.1 Hz), 8. 34
(1H,d,J=6.9Hz),8.76(0.5H,br),8.88(0.5H,br), 1 2.0(1 H,br).
mass:478(M+1) + .

Working Example No.1 72

45

[0548] According to the procedure described in the working example No.1 71 , the compound of the working example

No.1 65 was used to afford the titled compound.

mass:478(M+1) + .

50 Working Example No.1 73

[0549] According to the procedure described in the working example No.1 71 , the compound of the working example

No.1 63 was used to afford the titled compound.

mass:478(M+1)+.

55

Working Example No.1 74

[0550] A mixture of the compound (25 mg) of the working example No. 170 and 4N hydrochloric acid-dioxane (6 ml)

170

EP 1 199 306 A1

was stirred for 15 minutes at room temperature. The reaction mixture was concentrated and then dried to afford the

titled compound (7 mg) as a white solid.

1 H-NMR(DMSO-d 6 )

1 .07-1 .1 4(1 H,m),1 .89-1 .97(1 H ; m). 2.25-2. 41 (3H,m),2.42-2.58 (1 H,m),3. 04-3. 79(7H,m),4. 80-4.86(1 H,m),7. 09-7.1 1
5 (1 H,m), 7.31 -7. 34(2H,m), 7.47(1 H,t,J=7.8Hz),8.26-8.29(2H,m),9.1 6 (2H,br),10.1 (1 H,s),1 0.9(1 H.br).
mass:378(M+1)+.

Working Example No.1 75

10 [0551] According to the procedure described in the working example No.1 74, the compound of the working example
No.1 73 was used to afford the titled compound.
mass:378(M+1)+.

Working Example No.1 76

15

[0552] According to the procedure described in the working example No.1 74, the compound of the working example

No.1 71 was used to afford the titled compound.

mass:378(M+1)+.

20 Working Example No.1 77

[0553] According to the procedure described in the working example No. 174, the compound of the working exaple

No.1 72 was used to afford the titled compound.

mass:378(M+1)+.

25

Working Example No.1 78

[0554] According to the procedure described in the working example No. 84(2), the titled compound (5 mg) was
prepared from the hydrochloride of racemic compound (5 mg) of the working example No.1 74 and tert-butyl N-(2-ox-
30 oethyl) carbamate (8 mg).
1 H-NMR(CDCI 3 )

1 .22-1 .42(1 H,m),1 .45(9H,s),1 .82-1 .89(1 H,m), 2.29-2. 49 (3H : m),2.51 -2.80(4H,m),2.81 -2. 98(2H,m), 3.22-3. 34(3H,m),
3.41 -3.49(1 H,m),3.71 -3.81 (1H ! m),4.79(1H,dd,J=5.4,11 Hz), 5.04(1 H,br), 6. 82(1 H ,s),6. 93(1 H,d, J=5.7Hz), 7. 46(1 H,t,
J=7.8Hz ),7.54(1 H,d,J=7.2Hz),8.1 0(1 H,d,J=5.4Hz), 8.30(1 H ; d,J=7.8Hz), 8.48(1 H,br),1 2.0(1 H,br).
35 mass:521(M+1)+.

Working Examples No.1 79-1 82

[0555] According to the procedure described in the working example No.1 83, the compounds of the working examples
40 from No.1 79 to No. 1 82 were prepared.

Working Example No.1 79

[0556] mass:460(M+1 )+.

45

Working Example No.1 80
[0557] mass:460(M+1 )+.
50 Working Example No.1 81
[0558] mass:460(M+1 )+.
Working Example No.1 82

55

[0559] mass:460(M+1)+.

171

EP 1 199 306 A1

Working Example No.1 83

[0560] According to the procedure described in the working example No. 1 78, the working exaple No. 1 77 and butylal-
dehyde (7 was used to afford the titled compound (7 mg) as a lightly yellow oil y compound.
5 1 H-NMR(CDCI 3 )

0.93(3H,t,J=7.2Hz),1 .25-1 .43(3H,m),1 .52(2 H quintet, J=7.8Hz),1 .71 -1 .91 (1 H ; m) ! 2.32-2.66(8H ! m) ! 2.75(1 H,t, J=7.2Hz),
2. 96(1 H,t,J=8.7Hz), 3.30-3.35(1 H,m), 3.42-3.48 (1H,m),3. 72-3. 82(1 H,m),4. 79(1 H,dd,J=5.4, 11 Hz), 6. 80 (1H,br), 6.96(1 H,d,
J=5.7Hz), 7.47(1 H,t,J=7.5Hz),7.54(1 H,d,J=7.5Hz),8. 1 0(1 H,d,J=5.7Hz), 8.34(1 H,d,J=8.1 Hz), 8.38(1 H,br),1 2.0(1 H,br).
mass: 434(M+1)+.

10

Working Examples No.184-190

[0561] According to the procedure described in the working example No.1 83, the compounds of the working examples
from No. 184 to No. 190 were prepared.

15

Working Example No.1 84
[0562] mass:434(M+1 )+.
20 Working Example No.1 85
[0563] mass:434(M+1 ) + .
Working Example No.1 86

25

[0564] mass:434(M+1)+
Working Example No.1 87
30 [0565] mass:561(M+1)+
Working Example No.1 88
[0566] mass:561(M+1)+.

35

Working Example No.1 89
[0567] mass:561(M+1)+.
40 Working Example No.1 90
[0568] mass:561(M+1) + .
Working Example No.1 91

45

[0569] According to the procedure described in the working example No.1 93, the compound of the working example
No.1 87 was used to afford the titled compound.
mass:461 (M+1)+.

50 Working Example No.1 92

[0570] According to the procedure described in the working example No.1 93, the compound of the working example
No.1 88 was used to afford the titled compound.
mass:461 (M+1)+.

55

Working Example No.1 93

[0571] According to the procedure described in the working example No.1 33(2), the compound (6 mg) of the working

172

EP 1 199 306 A1

example No.1 89 was used to afford the hydrochloride of the titled compound (4 mg) as a yellow solid.
1 H-NMR(DMSO-d 6 )

1.04-1. 11 (1H,m),1. 65-2. 03(3H,m), 2. 1 9-2.59(9H,m),3.1 3-3. 34(3H,m),3. 36-4. 03(6H ; m), 4.84(1 H,dd.J=5.4,1 0Hz), 7.33
(1 H,d,J=7.2Hz),7.47(1 H,t,J=7.8Hz),7-1 6-7.55(2H,m), 8.26(1 H,d,J=7.8Hz),8.31 (1 H,d,J=5.4Hz),9.52(1 H,br),1 0.3(1 H,b
5 rd,J=10Hz),10.8(1H,br),11 ,7(1H,br).
mass:461 (M+1)+.

Working Example No.1 94

10 [0572] According to the procedure described in the working example No.1 93, the compound of the working example
No.1 90 was used to afford the titled compound.
mass:461 (M+1)+.

Working Examples No.1 95-210

15

[0573] According to the procedure described in the working example No.1 83, the compounds of the working examples
from No.1 95 to No. 21 0 were prepared.

Working Example No.1 95

20

[0574] mass: 488 (M+1)+.
Working Example No.1 96
25 [0575] mass:488(M+1) + .
Working Example No.1 97
[0576] mass:488(M+1 )+.

30

Working Example No.1 98
[0577] mass: 48B(M+1)+
35 Working Example No.1 99
[0578] mass:504(M+1 ) + .
Working Example No.200

40

[0579] mass:504(M+1)+.
Working Example No.201
45 [0580] mass: 504 (M+1)+.
Working Example No.202
[0581] mass:504(M+1)+.

50

Working Example No.203
[0582] mass: 494 (M+1)+.
55 Working Example No.204
[0583] mass:494(M+1 ) + .

173

EP 1 199 306 A1

Working Example No.205
[0584] mass:494(M+1 )+.
5 Working Example No.206
[0585] mass:494(M+1 )+.
Working Example No.207

10

[0586] mass:551(M+1)+.
Working Example No.208
15 [0587] mass:551(M+1)+
Working Example No.209
[0588] mass:551 (M+1 )+.

20

Working Example No.21 0

[0589] mass:551 (M+1 )+.

25 Working Examples No.21 1-240

[0590] According to the procedure described in the working example No.1 78, the compounds of the working examples
from No.21 1 to No. 240 were prepared.

30 Working Example No.21 1

[0591] mass:434(M+1)+.

Working Example No.21 2

35

[0592] mass:448(M+1)+.
Working Example No.21 3
40 [0593] mass:482(M+1)+.
Working Example No.21 4
[0594] mass:462(M+1 )+.

45

Working Example No.21 5
[0595] mass:420(M+1 )+.
50 Working Example No.21 6
[0596] mass:518(M+1)+.
Working Example No.21 7

55

[0597] mass:518(M+1)+.

174

EP 1 199 306 A1

Working Example No.21 8
[0598] mass: 448 (M+1)+
5 Working Example No.21 9
[0599] mass: 446 (M+1)+
Working Example No.220

10

[0600] mass:474(M+1)+.
Working Example No.221
15 [0601] mass:420(M+1)+
Working Example No.222
[0602] mass:462(M+1 )+.

20

Working Example No.223
[0603] mass:507(M+1 )+.
25 Working Example No.224
[0604] mass:512(M+1) + .
Working Example No.225

30

[0605] mass:512(M+1)+.
Working Example No.226
35 [0606] mass:484(M+1)+
Working Example No.227
[0607] mass:458(M+1 )+.

40

Working Example No.228
[0608] mass:504(M+1 )+.
45 Working Example No.229
[0609] mass:450(M+1 ) + .
Working Example No.230

50

[0610] mass:432(M+1) + .
Working Example No.231
55 [0611] mass:519(M+1)+.

175

EP 1 199 306 A1

Working Example No.232
[0612] mass:457(M+1)+.
5 Working Example No.233
[0613] mass:471(M+1)+.
Working Example No.234

10

[0614] mass:469(M+1)+.
Working Example No.235
15 [0615] mass:469(M+1)+
Working Example No.236
[0616] mass:469(M+1)+.

20

Working Example No.237
[0617] mass:452(M+1)+.
25 Working Example No.238
[061 8] m ass :472 (M+1 ) + .
Working Example No.239

30

[0619] mass:458(M+1)+.
Working Example No.240
35 [0620] mass:522(M+1)+
Working Example No.241

[0621] According to the procedure described in the working example No. 133(2), the compound (4 mg) of the working
40 example No. 178 was used to afford the hydrochloride of the titled compound (4 mg).
1 H-NMR(CD 3 OD)

1 .14-1 .28(1 H,m),1 .51 -1 .76(1 H ; m), 2.30-2. 48(3H,m),2.62-2. 75 (2H,m),3. 42-3. 76(1 OH ,m),4. 95(1 H,dd,J=5.7,1 1 Hz), 7. 55

(1 H,br), 7.57-7. 59(3H,m),8. 04-8. 07(1 H,m), 8. 30(1 H,d,J=6.6Hz).

mass:421(M+1)+

45

Working Examples No.242-247

[0622] According to the procedure described in the working example No.1 78, the compounds of the working examples
from No. 242 to No. 247 were prepared.

50

Working Example No.242
[0623] mass:500(M+1 )+.
55 Working Example No.243
[0624] mass:514(M+1) + .

176

EP 1 199 306 A1

Working Example No.244
[0625] mass : 514 (M+1)+.
5 Working Example No.245
[0626] mass:486(M+1 )+.
Working Example No.246

10

[0627] mass:472(M+1)+.
Working Example No.247
15 [0628] mass:484(M+1)+
Working Example No.248

[0629] According to the procedure described in the working example No. 249, the title compound was prepard.
20 mass:496(M+1)+.

Working Example No.249

[0630] The hydrochloride of the racemic compound (5 mg) of the working example No. 1 74 was dissolved in acetone-
25 water (2:1) (0.3 ml) and sodium acetate (4 mg) was added. The whole was cooled to 0 °C and 2,6-dichlorobenzoyl

chloride (2 uJ) was added. The reaction mixture was stirred for 4 hours and water was added. The whole was extracted

with chloroform and the organic layer was washed with water and saturated brine and dried over magnesium sulfate.

After filtration, the filtrate was concentrated to afford a residue, which was purified by TLC (Merck Art5744) eluted with

chloroform-methanol (20:1 ) to afford the titled compound (5 mg) as a white solid.
30 1H-NMR(CDCI 3 )

1.21-1. 36(1 H,m), 2. 06-2.1 8(1 H,m), 2.33-2. 64(4H,m), 3. 24-4.03(6H,m),4.21 -4. 27(1 H,m),4.74-4. 83(1 H,m), 6. 74(0.5H,s),
6. 82(0.5H ; s), 6. 88(0. 5H,d,J=5.7Hz), 6.94(0. 5H,d,J=5.7Hz), 7.23 -7.38(3H,m),7.45-7.77(2H,m),8.1 6(1 H,dd,J=5.4,12Hz),
8.31 (1 H,tJ=8.4Hz), 8.53(1 H,s),1 1 .8(0.5H,s),11 .9(0.5H,s).
mass:550(M+1)+.

35

Working Examples No.250-253

[0631] According to the procedure described in the working example No.249, the compounds of the working examples
from No. 250 to No. 253 were prepared.

40

Working Example No.250
[0632] mass:488(M+1 )+.
45 Working Example No.251
[0633] mass:483(M+1 ) + .
Working Example No.252

50

[0634] mass:483(M+1)+.
Working Example No.253
55 [0635] mass:483(M+1)+.

177

EP 1 199 306 A1

Working Example No.254
[0636]

5 (1) According to the procedure described in the working example No. 264(3), the compound (3.8 g) of the working

example from No. 264(1 ) and enoltriflete (which was prepared from 1 -benzyl-4-piperidon, lithium diisopropylamide,
N-phenyl trifluoromethanesulfonimide and tetrahydrofuran according the ordinaly procedure) were used to afford
a brown oily compound (1 .9 g).

(2) According to the procedure described in the working example No. 80(2) and (3), the compound obtained above
10 in (1) was used to provide the titled compound (230 mg) as a white solid.

1 H-NMR(DMSO-d 6 )

1 .28(1 H, m),2. 20-2. 80(7H,m), 3. 22(1 H,d,J2.6Hz), 3.45 (1 H,m), 3.67(2H,s),3.78(1 H p m),4.79(1 H ,dd,J=5.6.1 1 Hz),
6.36(1 H,br), 6. 88(1H,s),7.00(1H,d,J=5.6Hz),7.20-7.50(6H,m),7.50(1H,d, J=7.9Hz),8.1 0(1 H,d,J=5.6Hz),8.35(1 H,
d,J=7.9Hz),8.86 (1 H,s), 12.0(1 H,br).
15 mass:480(M+1)+.

Working Example No.255

[0637] The compound (1 60 mg) of the working example from No.254 was subjected to the reaction described in the
20 re f erence example No. 3 to afford a white solid (52 mg).
1 H-NMR(DMSO-d 6 )

1 .32(1 H,m),1 .70-2.00(4H,m),2.03(2H,m),2.25-2.80(4H,m) 3.08(2H,m),3.49(1 H,m),3.60(2H,s),3.81 (1 H,m),4.82(1 H,
dd, J=5.6,1 1 Hz), 6. 72(1 H, s), 6. 92(1 H,d,J=5.2Hz), 7.20-7.50 (5H, m), 7.49(1 H,t, J=7.9Hz), 7. 55(1 H ,d,J=7.9Hz), 8. 07(1 H,
s,),8. 15(1H,d,J=5.2Hz),8.40(1H,d,J=7.9Hz),12.0(1 H,br).
25 mass:482(M+1)+.

Working Example No.256

[0638] 1 -benzyl-3-piperidone was subjected to the reaction described in the working example No.254 to afford a
30 white solid (52 mg).
1 H-NMR(DMSO-d 6 )

1.30(1H,m), 2.20-2.80(7H,m), 3.35(1 H,d,J=2.0Hz), 3.48 (1H,m), 3.72(2H,s), 3.76(1H,m), 4.81 (1 H,dd,J=5.7,11 Hz),
6.44(1 H,m), 6.78(1 H,s), 6.95(1 H,dJ=5.6Hz), 7.20-7.40(5H,m), 7.49(1 H,d, J=7.9Hz), 7.53(1 H,d, J=7.9Hz), 8.11 (1H,d,
J=5.6Hz), 8.35(1 H,d,J= 7.9Hz), 8.52(1 H,s), 12.0(1 H,br).
35 mass : 480 (M+1)+.

Working Example No.257

[0639] The compound (30 mg) of the working example No. 56 was subjected to the reaction described in the reference
40 example No. 3 to afford a white solid (12 mg).
1 H-NMR(DMSO-d 6 )

1 .20-1.40(1 H,m),1.60-2.20(5H ; m), 2.20-2. 70(3H,m),2.80-3. 00 (3H, m), 3. 45(1 H,m),3.55(2H, s),3. 75(1 H,m),4. 78(1 H,dd,
J=5.6,11 Hz),6.71(1H,s),6.87(1H,d,J=5.2Hz),7.10-7.40(5H,m),7.47 (1 H,t,J=7.5Hz),7.54(1 H,d,J=7.9Hz),8.08(1 H,d,
J=5.2Hz),8.12(1 H,s), 8. 34(1 H, d,J=5.2Hz), 12.0(1 H,br).
45 mass:482(M+1)+.

Working Example No.258

[0640] According to the procedure described in the working example No. 260, the compound (1 80 mg) of the working
50 example No.256 was used to afford a yellow solid (1 7 mg).
1 H-NMR(DMSO-d 6 )

1 .25(1 H,m), 2.20-2. 70(5H,m),3. 01 (2H,m),3.45(1 H,m),3.70 (2H,s),3.75(1 H,m),4.79(1 H,dd,J=5.6,1 1 Hz),6.48(1 H,m),
6.67(1 H , s), 6. 98(1 H,d,J=5.2Hz), 7.46(1 H,t,J=7.9Hz), 7.52(1 H,s), 7. 58(1 H,d, J=7.9Hz),8. 30(1 H,dJ=7.9Hz),1 2.0(1 H ,br).
mass:390(M-i-1) + .

55

Working Example No.259

[0641] According to the procedure described in the working example No. 261 , the compound (20 mg) of the working

178

EP 1 199 306 A1

example No. 258 was used to afford a white solid (5 mg).
1 H-NMR(DMSO-d 6 )

1 .25(1 H, m),2.20(3H,s),2. 30-2. 80(5H,m),3. 40-3. 90(4H,m), 4.42(2H,m),4.81 (1 H,dd,J=5.6,11 Hz), 6.50(1 H,m), 5. 82(1 H,
s),7.0 0(1 H,d,J=5.2Hz), 7.48(1 H ,t,J=7.9Hz), 7.55(1 H,d,J=7.9Hz),8.20( 2H,m),8.35(1 H,d,J=7.9Hz) ; 1 1 .9(1 H,br).
5 mass:432(M+1)+.

Working Example No.260

[0642]

10

(1) A mixture of the compound (280 mg) of the working example No. 254, chloroethyl chloroformate (100 mg),
triethylamine (71 mg) and chloroform (5 ml) was stirred for 30 minutes at room temperature. The reaction mixture
was concentrated to afford a residue, which was purified by column chromatography on silica gel (Wakogel C-200)
eluted with chloroform-methanol (100:0-98:2) to affod a solid compound (295 mg).

15 (2) The compound (295 mg) obtained above in (1) was dissolved in methanol (5 ml) and the mixture was refluxed

for 3 hours. The reaction mixture was cooled to room temperature and saturated aqueous sodium hydrogencar-
bonate was added. The whole was extracted with chloroform. The organic layer was washed with brine and then
dried over magnesium sulfate. After filtration, the filtrate was concentrated to afford a residue, which was purified
by column chromatography on silica gel (FL60D Fujisilysia.Co.) eluted with chloroform-methanol (100:0-95:5) to

20 affod a light yellow solid compound (1 60 mg).

1 H-NMR(DMSO-d 6 )

1 .28(1H,m),2.40(3H ! m),2.62(1H,m),3.12(2H,m),3.45(1H,m),3.59 (2H,s), 3.77(1 H,m), 4.80(1 H,dd,J=5. 6,1 1 Hz),
6.42(1H,m),6.81(1H ,s),7.02(1 H,d,J=5.3Hz), 7.26(1H,s), 7.46(1 H,t,J=7.9Hz), 7.55(1 H,d,J=7.9Hz),8.13(1 H,d,
J=5.3Hz),8.33(1H,s,),8.35(1H,d,J=7.9 Hz),1 2.0(1 H,br).
25 mass:390(M+1)+.

Working Example No.261

[0643] A mixture of the compound (30 mg) of the working example No.260, acetyl chloride (6.6 triethylamine
30 (13(_lI) and chloroform (3 ml) was stirred for 1 hour at room temperature. The reaction mixture was added saturated
aqueous sodium hydrogencarbonate and then extracted with chloroform. The organic layer was washed with brine
and then dried over magnesium sulfate. After filtration, the filtrate was concentrated to afford a residue, which was
purified by TLC (Merck AH5744) eluted with chloroform-methanol (9:1) to afford a white crystal solid (5 mg).
1 H-NMR(DMSO-d 6 )

35 1 .25(1 H,m)1 2.22(3H,s), 2.20-2. 80(5H,m),3.40-3.95(4H,m), 4.35(2H,m),4.82(1 H,dd, J=5.6,1 1 Hz), 6.40(1 H ,m),6.80(1 H,
s),7.0 3(1 H,d,J=5.6Hz), 7.49(1 H,t,J=7.9Hz), 7.57(1 H,t,J=7.9Hz), 8. 20( 2H, m),8. 33(1 H ; d,J=7.9Hz),1 1 .9(1 H,br).
mass:432(M+1) + .

Working Example No.262

40

[0644] Accrodingto the procedure described in the working example No. 84(2), the compound (20 mg) of the working

example No.260 was used to afford a white solid (3 mg).

1 H-NMR(DMSO-d 6 )

1.05-2.20(14H,m), 2.20-2.90(6H,m), 3.22-3. 50(3H,m), 3.70-3.82(1 H,m), 4.78(1 H ; dd,J=5. 8,1 1 Hz), 6.37(1H,m), 6.77
45 (1 H,s),7.0 1 (1 H,d,J=5.4Hz),7.54(1 H,d,J=7.8Hz),8.12(1 H,d,J=5.4Hz),8.32( 1 H,d,J=7.8Hz),12.0(1 H,s).
mass:472(M+1)+.

Working Example No.263

so [0645] Accroding to the procedure described in the working example No.262, the titled compound was prerpared.
mass:506(M+1)+.

Working Example No.264

55 [0646]

(1 ) The hydrochloride of methyl 4- chloropyridine- 2-carboxylate (3 g) was added to dioxane (1 40 ml). To the mixture
was added hexabutylditin (8.4 g) and tetrakistriphenyl phosphine palladium. The whole was refluxed for 12 hours

179

EP 1 199 306 A1

under an atmosphere of nitrogen. The reaction mixture was cooled to room temperature and a 10% solution of
potassium fluoride was added. The whole was stirred for 30 minutes and diluted with ether. After filtration, the
filtrate was washed with brine and then dried over magnesium sulfate. After filtration, the filtrate was concentrated
to afford a residue, which was purified by column chromatography on silica gel (Wakogel C-200) eluted with hexane-
5 ethyl acetate (1 :0~2:1) to afford a colorless oily compound (0.9 g).

(2) Accroding to the procedure described in the working example No. 80(2) and (3), the compound (6.3 g) obtained
above in (1 ) was used to afford an oily compound (2.8 g).

(3) The mixture of the compound (60 mg) obtained above in (2), 3-bromopyridine (47 mg), 2-dicyclohexylphosphyno-
biphenyl (21 mg), lithium chloride (9 mg), tris(benzylidenacetone)dipalladium (21 mg) and tetrahydrofuran (2 ml) was

10 refluxed overnight. To the reaction mixture was added a 10% solution of potassium fluoride and chloroform. The

organic layer was separated and washed with water and saturated brine and then dried over magnesium sulfate.
After filtration, the filtrate was concentrated to afford a residue, which was purified by TLC (Merck Art5744) eluted
with chloroform-methanol (9:1) to affod a white crystal (5 mg).
1 H-NMR(DMSO-d 6 )

15 1 .1 0-1 .20(1 H,m), 2. 33-2.40(1 H,m),2.40-2.78<2H,m>,3.28-3.33 (1 H,m),3.53(1 H,m),4.84(1 H,m),7.31 (1 H,d,J=7.7Hz),

7.43-7.49 (1 H,m),7.56(1 H,dd,J=4.5,7.7Hz),7.61 (1 H,s),8,1 0(1 H,dd,J=2.3, 7.7Hz),8.30(1 H,d,J=7.7Hz),8.41 (1 H,d,
J=5.5Hz),8.68(1 H,d,J=5. 5Hz),8.91 (1 H,d,J=2.3Hz),1 0.0(1 H,s),1 1 .0(1 H,br).
mass:386(M+1)+.

20 Working examples No.265 to 277

[0647] According to the procedure described in the compound of working example No. 264, the compounds f working
example No.265 to No. 277 were obtained.

25 Working example No.265

[0648] mass:385(M+1 ) + .

Working example No.266

30

[0649] mass:423(M+1)+.
Working example No.267
35 [0650] mass:386(M+1)+.
Working example No.268
[0651] mass:386(M+1)+.

40

Working example No.269
[0652] mass:392(M+1 )+.
^5 Working example No.270
[0653] mass:391(M+1) + .
Working example No.271

50

[0654] mass:465(M+1)+.
Working example No.272
55 [0655] mass:435(M+1)+.

180

EP 1 199 306 A1

Working example No.273
[0656] mass:435(M+1 )+.
5 Working example No.274
[0657] mass:391(M+1)+.
Working example No.275

10

[0658] mass:389(M+1)+.
Working example No.276
15 [0659] mass:407(M+1)+
Working example No.277
[0660] mass : 445(M+1)+.

20

Working example No.278

[0661] According to the procedure described in the compound of working example No. 261 , the compound of working
example No. 82 was used to afford a white solid (9 mg).
25 1 H-NMR(DMSO-d 6 )

0.89(3H ) t ) J=7.3Hz) ) 1.15(1H ) m) ) 1.57(2H 5 q ) J=7.3Hz),2.15(2H 5 q ) J=7.3Hz),2. 20-2. 60(3H,m) ; 3.30(1 H,m),3. 55(1 H,m),
4.24(1 H,d, J=6.0Hz),4.82(1 H,dd,J=5.6,11 Hz), 6. 92(1 H,d,J=5.6Hz),7.13(1 H, s), 7. 46(1 H,t,J=7.9Hz),7.48(1 H,d,J=
7. 9Hz), 8.23(1 H,d,J=5.6Hz) ,8.30(1 H,d,J=7.9Hz), 8. 42(1 H,t,J=6.0Hz), 9. 97(1 H,s),1 1 .3(1 H, br).
mass:408(M+1)+.

30

Working example No.279

[0662] The compound (30 mg) of the working example No. 80 and butanoyl chloride were dissolved in dimethylfor-
mamide and the mixture was stirred for 30 minutes at 90 °C. The reaction mixture was diluted with chloroform, washed
35 with aqueous saturated sodium hydrogencarbonate, saturated brine and then dried over magnesium sulfate. After
filtration, the filtrate was concentrated to afford a residue, which was purified by TLC (Merck Art5744) eluted with
chloroform-tetrahydrofuran (7:3) to afford white crystals (8 mg).
1 H-NMR(DMSO-d 6 )

0.97(3H,t,J=7.3Hz),1 .25(1 H,m),1 .70(2H,q,J=7.3Hz),2.30-2.60 (1 H,m), 2. 40(2H,q,J=7.4Hz), 2.30-2. 55(2H,m),2. 60(1 H,
40 m),3.45 (1H,m), 3.79(1H,m), 4.80(1 H,dd,J=5.6,1 1 Hz),5.1 3(2H,s),6.84 (1H,s), 6.96(1 H,d,J=5.5Hz), 7.49(1H,t,
J=7.9Hz), 7.55(1 H,d,J=7. 9Hz), 8.1 9(1 H,d,J=5.5Hz), 8.31 (1 H,d,J=7.9Hz), 11.9(1H,br).
mass : 409 (M+1) + .

Working example No.280

45

[0663] According to the procedure described in the compound of working example No.279, the compound of working

example form No.280 was prepared.

mass:449(M+1)+.

50 Working example No.281

[0664] According to the procedure described in the compound of working example No.278, the compound of working
examples form No.281 was obtained,
mass: 448(M+1)+.

55

181

EP 1 199 306 A1

Working example No.282
[0665]

(1) A mixture of 2-aminopyridine-4-carboxylic acid (1 g), thionylchloride (2.8 ml) and methanol (36 ml) was refluxed
overnight. The reaction mixture was concentrated to afford a residue. Saturated aqueous sodium hydrogencar-
bonate was added to the residue and then extracted with chloroform. The organic layer was washed with brine
and then dried over magnesium sulfate. After filtration, the filtrate was concentrated to afford a residue, which was
purified by column chromatography on silica gel (Wakogel C-200) eluted with chloroform-methanol (100:0-98:2)
to afford the titled compound (1 .05 g).

(2) A mixture of the compound (1 .8 g) of the reference example No. 3, trichloroacetic anhydrate (0.35 ml), triethyl-
amine (0.2 ml), methylen chloride (5ml) and tetrahydrofuran (10 ml) was stirred for 2 hours at room temperature.
Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture and then extracted with chlo-
roform. The extract was washed with brine and then dried over magnesium sulfate. After filtration, the filtrate was
concentrated to afford a residue, which was purified by column chromatography on silica gel (Wakogel C-200)
eluted with chloroform-tetrahydrofuran (9:1-8:2) to afford an amorphous compound (2.92 g).

A mixture of the compound (1 .77 g) obtained above, the compound (1 .05 g) obtained above in (1), DBU (1
ml) and dimethylsulfoxide (8 ml) was stirred for 3 hours at 1 00 °C. The reaction mixture was diluted with chloroform
and was washed with water and brine and then dried over magnesium sulfate. After filtration, the filtrate was
concentrated to afford a residue, which was purified by column chromatography on silica gel (Wakogel C-200)
eluted with chloroform-methanol (97:3) to afford the desired compound (1 .21 g).

(3) A mixture of the compound (300 mg) obtained above in (2), 1 N sodium hydroxide solution (1 0 ml) and methanol
(3 ml) was stirred for 1 hour at 90 °C. The pH of the reaction mixture was adjusted to 4 with 1 N hydrochloric acid
and then extracted with chloroform. The organic layer was washed with brine and then dried over magnesium
sulfate. After filtration, the filtrate was concentrated to afford a residue, which was washed with chloroform-ethyl
acetate to afford a white solid compound (80 mg).

(4) According to the procedure described in the compound of working example No. 409(1 ), the compound (1 8 mg)
obtained above in (3) was used to afford the titled compound (5 mg) as a white solid.
1 H-NMR(DMSO-d 6 )

0.92(3H,t,J=7.2Hz),1 .13(1 H,m),1 .32(1 H,m),1 .53(2H,m), 2. 20-2. 70(3H,m), 3.20-3. 70(4H,m), 4. 85(1 H,dd,

J=5.6 ; 11 Hz),7.32 (1 H,d,J=7.9Hz),7.38(1 H,d 5 J=5.2Hz) ; 7.49(1 H,t,J=7.9Hz), 7.75(1 H,s),8.30(1 H,d =7.9Hz),8.43

(1H,d,J=5.2Hz),8.70(1H,t,J=6.7Hz ),1 0.1 (1 H,s),1 0.8(1 H,br).

mass:408(M+1) + .

Working examples No.283 to No.286

[0666] According to the procedure described in the compound of working example No.282, thecompounds of working
examples form No.283 to No.286 were obtained.

Working example No.283

[0667]

mass: 434(M-i-1) + .

Working

example No. 284

[0668]

mass: 443 (M+1)+

Working example No. 285

[0669]

mass:443(M+1) + .

Working

example No.286

[0670] mass:443(M+1 )+.

182

EP 1 199 306 A1

Working example No.287
[0671 ]

5 (1) According to the procedure described in the compound of reference example No.1 , isoquinoline-3-carboxylic

acid (90 mg) was used to afford a yellow solid compound (14 mg).

(2) According to the procedure described in the compound of working example No. 79, the compound (14 mg)

obtained above in (1) was used to afford the titled compound (13 mg) as a white solid.

lH-NMR(DMSO-d 6 )

10 1 .10-1 .20(1 H,m), 2. 25-2. 50(2H,m), 2.58-2. 70(1 H,m),3.20-3.40 (1 H,m),3. 48-3. 62(1 Km), 4. 83(1 H,dd,J=5.6,1 0Hz),

7.33(1 H,d, J=7.9Hz),7.49(2H ) m) ) 7.70(1H ) t ) J=7.9Hz) ) 7.87(1H,d ! J=7.9Hz),8 .02(1 H,s),8. 07(1 H,d,J=7.9Hz),8. 31
(1 H,d,J=7.9Hz),9.1 8(1 H,s), 9.70(1 H,br), 9. 90(1 H,s).
mass:359(M+1)+.

15 Working example No.288

[0672]

(1) A mixture of isoquinoline 3- carboxylic acid (300 mg), platinum oxide (30 mg), 4N hydrochloric acid-dioxane (5
20 ml) and methanol (5 ml) was stirred for 6 hours at room temperature. The reaction vessel was filled with hydrogen.

The reaction mixture was filtered by celite. The filtrate was concentrated to afford a crude product (32 mg).

(2) According to the procedure described in the compound of working example No.287, the compound (130 mg)
obtained above in (1) was used to afford the titled compound (23 mg) as a white solid.
1 H-NMR(DMSO-d 6 )

25 1 .00-1 .20(1 H,m),1 .60-1 .80(4H,m), 2.20-2. 70(7H,m),3.20-3. 35 (1 H,m), 3.45-3. 60(1 H,m),4.77(1 H,dd,J=5.5,1 0Hz),

6.95(1 H,s), 7.28(1 H,d,J=7.9Hz), 7.43(1 H,t,J=7.9Hz), 8.00(1 H,s) ,8.29(1 H,d,J=7.9Hz), 9.71 (1H,s), 11.2(1 H,br).
mass : 363 (M+1) + .

Working Example No.289

30

[0673]

(1 ) A solution of dimethylacetal of 4-pyridinecarboxylaldehyde (1 5 g) in tetrahydrofuran (300 ml) was cooled to -78
°C. To the solution was added a solution of n-butyllithium in hexane (1 .6 M, 73 ml). The reaction temperature was

35 raised from -78 °C up to 0 °C. Tert-butyldimethylsilylether of 3-bromobutanol (25 g) was added at 0 °C. The whole

was stirred for 3 hours at the same temperature and then warmed up to room temperature. To the reaction mixture
was added saturated aqueous sodium hydrogencarbonate. The whole was extracted with chloroform. The organic
layer was washed with saturated brine and dried over magnesium sulfate. After filtration, the filtrate was concen-
trated to afford a residue, which was purified by column chromatography on silica gel (Wakogel C-200) eluted with

40 hexane-ethyl acetate (2:1) to afford an oily compound (17 g).

(2) According to the procedure described in the reference example No. 7, the compound (7 g) obtained above in

(1) was used to afford an oily compound (3.9 g).

(3) According to the procedure described in the reference example No. 8, the compound (3 g) obtained above in

(2) was used to afford a brown oily compound (7 g).

45 (4) To water-tetrahydrofuran (1 :1 0) was added the compound (7 g) obtained above in (3) and triphenylphosphine

(5.8 g). The mixture was stirred for 2 hours at 50 °C. The reaction mixture was concentrated to afford a residue,
which was purified by column chromatography on silica gel (FL60D Fujisilysia.Co.) eluted with chloroform-methanol
(100:0-98:2) to afford a brown oily compound (2.1 g).

(5) The compound (2.1 g) obtained above in (4) in chloroform (1 0 ml) was added to formic acid (5 ml). The mixture
50 was stirred for 2 hours at 80 °C. The reaction mixture was concentrated to afford a residue, which was dissolved

in methanol (1 0 ml). To the solution was added sodium borohydride (7.4 g) and the mixture was stirred for 1 hour
at room temperature. The reaction mixture was diluted with chloroform and washed with brine and then dried over
magnesium sulfate. After filtration the filtrate was concentrated to afford a residue, which was purified by column
chromatography on silica gel (FL60D Fujisilysia. Co.) eluted with chloroform-methanol (100:0-98:2) to afford the
55 titled compound (0.57 g).

(6) A mixture of the compound (0.57 g) obtained above in (5), p-nitrobenzenesulfonyl chloride (7 g), dimethylami-
nopyridine (0.71 g) and chloroform (5 ml) was stirred for 2 hours at room temperature. The reaction mixture was
diluted with chloroform and washed with saturated aqueous sodium hydrogencarbonate and brine and then dried

183

EP 1 199 306 A1

over magnesium sulfate. After filtration, the filtrate was concentrated to afford a residue, which was purified by
column chromatography on silica gel (Wakogel C-200) eluted with chloroform -methanol (1 00:0-98:2) to afford the
titled compound (0.73 g).

(7) A mixture of the compound 0.73 g) obtained above in (6), manganese dioxide (50 mg),a 30% solution (5 ml)
5 of hydrogen peroxide and chloroform (20 ml) was stirred for 6 hours at room temperature. The reaction mixture

was diluted with chloroform and washed with saturated aqueous sodium hydrogencarbonate and brine and then

dried over magnesium sulfate. After filtration, the filtrate was concentrated to afford a residue, which was purified

by column chromatography on silica gel (Wakogel C-200) eluted with chloroform-methanol (100:0-98:2) to afford

the crystalline compound (0.78 g).
10 (8) A mixture of the compound (0.78 g) obtained above in (7), trimethylsilylcyanide (0.66 ml) and acetonitrile-

chloroform was stirred for 3 hours at 80 °C. The residue was purified by column chromatography on silica gel

(Wakogel C-200) eluted with chloroform-methanol (1 00:0-98:2) to afford the crystalline compound (0.71 g).

(9) Accroding to the procedures described in the reference examples No. 4 and 5, the compound obtained above

in (8) was used to afford the titled compound (75 mg).
15 (1 0) Accroding to the procedure described in the reference example No.1 1 , the compound (75 mg) obtained above

in (9) was used to afford the titled compound (18 mg) as a light yellow solid and the compound (1 .4 mg) of the

working example No. 292 as a yellow solid.

1 H-NMR(DMSO-d 6 )

1 .25(1 H,m),1 .60-2.00(3H,m),2.20-2.60(4H,m),2.64(1 H,m), 3.15(2H,m), 3.45(1 H,m) ; 3.78(1 H,m), 4,1 8(1 H,t,
20 J=7.2Hz), 4.80(1H , dd, J=5.6,11Hz), 6.98(1H,s), 6.99(1 H,d, J=5.6Hz), 7.46(1 H,t,J=7 .9Hz), 4.55(1 H ; d,J=7.9Hz),

8. 11(11-1, d,J=5.6Hz), 8.39(1 H,d,J=7.9 Hz), 8.40(1 H,s), 1 2.0(1 H,br).
mass:378(M+1) + .

Working Example No.290

25

[0674] The compound (7 mg) of the working example No. 289 was dissolved in methanol (2 ml). To the solution were
added formalin (50 and stirred for 4 hours at room temperature. To the reaction mixture was added sodium boron
hydride (1 00 mg) and stirred for 1 hour at room temperature. To the reaction mixture, was added 1 N hydrochloric acid
to decompose the excess reagent. Saturated aqueous sodium hydrogencarbonate was added and then extracted with
30 chloroform. The organic layer was washed with saturated brine and then dried over magnesium sulfate. After filtration
the filtrate was concentrated to afford a residue, which was purified by column chromatography on silica gel (FL60D
Fujisilysia.Co.) eluted with chloroform-methanol (9:1) to afford the titled compound (3 mg) as a yellow solid.
1 H-NMR(DMSO-d 6 )

1 .25(1H,m),1 .55-2.1 0(4H,m),2.22(3H,s),2.20-2.40(3H,m), 2.65(1 H,m),3.1 4(1 H,m), 3.25(1 H,m), 3. 50(1 H,m),3. 79(1 H,
35 m),4.82 (1 H ; dd,J=5.6,1 1 Hz), 6. 89(1 H,s), 7.03(1 H,d,J=5.6Hz), 7.49(1 H,t, J=7.9Hz),7.56(1 H,d,J=7.9Hz),8.05(1 H,s),8.15
(1H,d,J=5.6Hz),8 .35(1 H,d,J=7.9Hz),1 2.0(1 H,br).
mass:392(M+1) + .

Working Example No.291

40

[0675] A mixture of the compound (7 mg) of the working example No. 289, acetic anhydride (6 mg), dimethylami-
nopyridine (5 mg) and chloroform (2 ml) was stirred overnight at room temperature. The reaction mixture was diluted
with chloroform and washed with saturated aqueous sodiun hydrogencarbonate and saturated brine and then dried
over magnesium sulfate. After filtration, the filtrate was concentrated to afford a residue, which was purified by TLC
45 (Merck Art5744) eluted with chloroform-methanol (7:3) to afford the titled compound (3 mg) as a solid.
1 H-NMR(DMSO-d 6 )

1 .25(1H,m),1 .80-2.1 0(3H, m),2. 11 (3H,s), 2.20-2. 70(4H,m),3.30-3.80(4H,m),4.60-5.20(2H,m),6. 60-6. 90(1 H,m),
7.40-7.60 (2H,m),8.00-8.40(2H,m),9.1 0(1 H,br),1 1 .9(1 H,br).

50 Working Example No.292

[0676] The titled compound was prepared in the last process for preparing the compound of the working example
No.289.

1 H-NMR (DMSO-d 6 )

55 1 .20-1.60(3H,m),2.10(2H,m),2.40(2H,m),2.60(1H,m), 2.90(2H,m),3.45(1 H,m),3.78(1 H,m),4.80(1 H,dd,J=5.6,1 1 Hz),
7.10-7.60(4H,m),8.00-8.40(3H ! m),11 .8(1H,br).
mass:376(M+1) + .

184

EP 1 199 306 A1

Working Example No.293
[0677]

5 (1) Accroding to the procedure described in the reference example No. 6, the compound (9 g) of the working ex-

ample No. 80(3) was used to afford a brown oily compound (8.5 g).

(2) According to the procedure described in the working example No. 80(4), the compound (8.5 g) obtained above
in (1) was used to afford a brown amorphous compound (4.7 g).

(3) According to the procedure described in the working example No. 84(1), the compound (250 mg) obtained
10 above in (2) was used to afford the titled compound (21 0 mg).

(4) A solution of ethyl di-o-tolylphosphono acetate (38 mg) in tetrahydrofuran (2 ml) was cooled to -78 °C. To the
solution was added a solution of the compound (43 mg) obtained above in (3) in tetrahydrofuran (1 ml). The whole
was stirred for 2 hours at -78 °C. To the reaction mixture was added saturated aqueous ammonium chloride. The
whole was warmed up to room temperature and extracted with chloroform solution. The organic layer was washed

15 with saturated brine and then dried over magnesium sulfate. After filtration, the filtrate was concentrated to afford

a residue, which was purified by column chromatography on silica gel (Wakogel C-200) eluted with chloroform-
methanol (100:0-97:3) followed byTLC (Merck Art5 744) eluted with chloroform-ethanol (9:1) to afford a colorless
oily compound (40 mg).

(5) A mixture of the compound (40 mg) obtained above in (4), 6N hydrochloric acid and tetrahydrofuran (5 ml) was
20 stirred for 15 minutes at room temperature. The reaction mixture was extracted with chloroform and washed with

saturated brine and then dried over magnesium sulfate. After filtration, the filtrate was concentrated to afford the

titled compound (19 mg) as a colorless solid.

1 H-NMR(DMSO-d 6 )

1 .1 5(3H,t,J=7.1 Hz),1 .09-1 .1 5(1 H,m),2.30-3.38(2H,m), 2.48-2. 56(1 H,m), 3.20-3. 31 (1 H,m),3.51 -3.55(1 H,m), 14.1 1
25 (2H,q, J=7.1Hz),4.79-4.85(1H ) m) ) 6.23(1H,d ) J=13Hz),7.04(2H,m) ! 7.30-7.32(2H,m),7.46(1H,t,J=7.7Hz),8.28-8.30

(2H,m), 9.99(1 H,s), 1 1 .0(1 H,br).
mass:407(M+1) + .

Working Example No.294

30

[0678]

(1 ) A solution of ethyl diethylphosphono acetate (22 mg) in tetrahydrofuran (2 ml) was cooled in an ice-bath. Sodium
hydride (4 mg) was added and the mixture was stirred for 30 minutes. To the mixture was added a solution of the

35 compound (43 mg) of the working example No. 293(3) in tetrahydrofuran (1 ml). The whole was stirred for 2 hours

and then aqueous saturated ammonium chloride solution was added. The mixture was warmed up to room tem-
perature and extracted with chloroform. The organic layer was washed with saturated brine and then dried over
magnesium sulfate. After filtration, the filtrate was concentrated to afford a residue, which was purified by column
chromatography on silica gel(Wakogel C-200) eluted with chloroform- methanol (1 00:0-97:3) to afford a white solid

40 (42 mg).

(2) According to the procedure described in the working example No. 293(5), the compound (42 mg) obtained
above in (1 ) was ued to afford the titled compound (21 mg) as a white solid.

1 H-NMR(DMSO-d 6 )

1 .00-1 .20(1 H,m),1 .28(3H,t,J=7.1 Hz),2.20-2.40(2H,m), 2.40-2. 60(1 H,m), 3.20-3. 40(1 H,m),3.45-3.60(1 H,m),4.23
45 (1H,q, J=7.1Hz),4.84(1H,m),6.78(1H,d,J=16Hz),

7.33(1 H, d,J=7.9Hz), 7.40-7. 50(3H,m), 7.57(1 H,d,J=1 6Hz), 8.30(1 H, d,J=7.9Hz), 8.36(1 H,d,J=5.6Hz),1 0.0(1 H,s),

10. 8(11-1, br).

mass:407(M+1) + .

50 Working Example No.295

[0679] To a solution of the compound (50 mg) of the working example No. 294(1) in chloroform (5 ml), were added
zinc chloride (27 mg) and sodium borohydride (7 mg). The reaction mixture was refluxed for 3 hours and treated
according to the procedure described in the working example No. 290. The titled compound (32 mg) was obtained as
55 a white solid.

1 H-NMR(DMSO-d 6 )

1 .00-1. 20(1 H,m), 2. 20-2. 60(3H ; m), 3.20-3. 60(2H,m), 4.1 7(2H,m),4.84(1 H,dd,J=5.6, 1 1 Hz),5.04(1 H,t,J=6.3Hz), 6.53
(1 H,d,J=1 6Hz),6.66(1 H,d,J=1 6Hz),7.1 5(1 H,d,J=5.3Hz), 7.22(1 H,s), 7.31 (1 H,d,J=7.9Hz),7.47(1 H,t,J=7.9Hz), 8.24(1 H,

185

EP 1 199 306 A1

d,J=5.3Hz),8.32(1 H,d,J=7.9Hz),9.94(1 H,s), 11 .3(1 H,br).
mass:365(M+1)+.

Working Example No.296

5

[0680] To a solution of the compound (30 mg) of the working example No. 294(1) in methanol (10 ml), were added
cuprous chloride (1 0 mg) and sodium borohydride (4 mg). The reaction mixture was stirred until the disappearance of
the starting material. The reaction mixture was treated according to the procedure described in the working example
No. 290. The titled compound (13 mg) was obtained as a white solid.
10 iH-NMR(DMSO-d 6 )

1.05-1. 25(1 H,m), 11 .1 5(3H,t,J=7.1 Hz), 2.20-2. 60(3H,m), 2.64(2H,tJ=7.1 Hz), 2.83(2H,t,J=7.1 Hz), 3.20-3.40(1 H,m),
3.45-3.60(1 H,m), 4.04(2H,q,J=7.1 Hz), 4.81 (1H,m) 6.96(1 H,d,J=5.3Hz), 7.1 1 (1 H,s), 7.30(1 H,d,J=7.9Hz), 7.45(1 H,d,
J=7.9Hz),8.19(1H,d,J=5.4Hz),8.30(1H,d,J=7.9Hz), 9.90(1 H,s),1 2.3(1 H,br).
mass:409(M+1)+.

15

Working Example No.297

[0681] The compound (60 mg) of the working example No. 293 was dissolved in chloroform (30 mL). To the solution,
was added a solution of diisopropylaluminum hydride in toluene (1 .0 M, 0.9 ml). The mixture was stirred for 30 minutes
20 at -30 to - 20 °C. The reaction mixture was treated according to the procedure described in the working example No.
290 to obtain the titled compound(1 7 mg) as a white solid.
1 H-NMR(DMSO-d 6 )

1 .25(1 H,m), 2.20-2. 70(3H,m),3. 30(1 H,m),3.53(1 H,m),4.1 5-4.40(2H,m),4.81 (1 H,dd,J=5.6,1 1 Hz), 5. 00(1 H,m), 6. 00(1 H,
m), 6.38(1 H,m),6. 89(1 H,d,J=5.4Hz), 7.1 2(1 H,s),7.31 (1 H,d,J=7.9Hz) , 7.45(1 H,t,J=7.9Hz),8.28(2H,m),9.90(1 H,s),1 1 .1
25 (1H,br).

mass:365(M+1)+.

Working Example No.298

30 [0682] A mixture of the compound (40 mg) of the working example No. 294, 2N aqueous sodium hydroxide solution
(5 ml), tetrahydrofuran (2 ml) and methanol (2 ml) was stirred for 1 hour at room temperature. To the reaction mixture,
was added 1 N hydrochloric acid to adjust the pH of the reaction mixture to 3. The whole was extracted with chloroform.
The organic layer was washed with saturated brine and then dried over magnesium sulfate. After filtration, the filtrate
was concentrated to afford a residue, which was purified by TLC (Merck Art5744, chloroform-methanol (9:1) followed

35 by recrystallization to afford the titled compound (22 mg) as a white solid.
1 H-NMR(DMSO-d 6 )

1 .00-1. 20(1 H,m), 2. 20-2. 60(3H ; m), 3.1 5(1 H,m), 3. 45-3.60(1 H,m), 4. 82(1 H,m), 6. 68(1 H,d,J=16Hz), 7.20-7. 60(5H ; m),

8.28(1 H,d,J=7.9Hz),8.35(1H,d,J=5.6Hz),1 0.2(1 H,s) ,1 0.9(1 H,br),1 2.8(1 H,br).

mass:379(M+1)+.

40

Working Example No.299
[0683]

45 (1)A mixture of the compound (727 mg) of the working example No. 7, DBU(1 .496 ml) and tetrahydrofuran (1 0 ml)

was cooled to 0°C and a solution of methanesulfonyl chloride (0.31 0 ml) in tetrahydrofuran (2 ml) was added. The
reaction mixture was stirred for 11 hours at room temperature and water was added. The whole was extracted with
chloroform. The organic layer was washed with water and saturated brine and then dried over magnesium sulfate.
After filtration, the filtrate was concentrated to afford a residue, which was purified by column chromatography on

50 silica gel (Wakogel C-200, hexane-ethyl acetate (1 :1 -0: 1 )) to afford a colorless amorphous compound (606 mg).

(2) According to the procedure described in the working example No. 133(2), the titled compound was prepared.
1 H-NMR(DMSO-d 6 )

1 .07-1 .14(1 H, m), 2. 29-2. 57(3H,m), 3.24-3. 88(2H,m),4. 79-4. 85(1 H,m),5. 58(1 H,d,J=1 1 Hz), 6.08(1 H,d,J=18Hz),
6.74(1 H,dd,J=1 1 ,18Hz), 7. 22-7.24(1 H,m),7.29-7.34(2H,m), 7.47(1 H,tJ=7.5Hz), 8.22-8. 27(2H,m),1 0. 1 (1 H.s),1 1 .0
55 (1H,br).

mass:335(M+1) + .

186

EP 1 199 306 A1

Working Example No.300
[0684]

5 (1) Asolution of the compound (80 mg) of the working example No. 294(1) in methylene chloride (5 ml) was cooled

in an ice -bath. Trif I uoro acetic acid (274 mg) and N-(methoxymethyl)-N-trimethylsilylmethyl)benzylamine (1 90 mg)
were added.

The reaction mixture was stirred for 3 hours and diluted with chloroform. The whole was washed aqueous saturated
sodium bicarbonate solution and saturated brine and then dried over magnesium sulfate. After filtration, the filtrate
10 was concentrated to afford a residue, which was purified by TLC (Merck Art5744, chloroform-methanol (9:1)) fol-

lowed by recrystallization to afford a light yellow oily compound (91 mg).

(2) According to the procedure described in the working example No. 293(5), the compound (91 mg) obtained

above in (1) was used to afford titled compound as a white solid (50 mg).

1 H-NMR(DMSO-d 6 )

15 1.24(1H,m),1 .24(3H ! t,H=7.4Hz),2.20-2.75(3H,m) ! 2.80(1H,m), 2.95(1 H,m), 3. 05(1 H,m), 3.1 9(1 H,m)1 3.45(1 H,m),

3.60-3.90(4H,m), 4.1 8(2H,q,J=7.4Hz),4.78(1 H,dd,J=5.6,1 1 Hz), 6. 93(1 H,s),7.03(1 H,d,J=5.6Hz), 7.1 0-7.45(5H,m),
7.50(1 H,t,J=7.9Hz), 7.55(1 H,d,J=7.9Hz), 8. 1 3(1 H,d,J=5.6Hz), 8.37(1 H,d,J=7.9Hz), 8.82(1H,s), 12.0(1H,br).
mass:540(M+1)+.

20 Working Example No.301

[0685] According to the procedure described in the working example No.300, the titled compound was prepared from

the compound of the working example No. 293(4).

mass:540(M+1)+.

25

Working Example No.302

[0686] A solution of the compound (30 mg) of the working example No. 300 in tetrahydrofuran (3 ml) was cooled in
an ice-bath. To the solution, were added a solution of lithium aluminum hydride in tetrahydrofuran (2 M, 56 ul) and a
30 solution of methanol in tetrahydrofuran (1 M, 0.22 ml). The reaction mixture was stirred for 30 minutes at room tem-
perature. According to the procedure described in the working example No. 290, the titled compound (less polar fraction)
(1 .2 mg) as a white solid and its diastereomer compound (2.3 mg) (more polar fraction), which is the compound of the
working example No. 303, were prepared.
H-NMR(DMSO-d 6 )

35 1 . 25(1H,m), 2.20-2. 60(3H, m),3. 30-4.40(1 2H,m),4. 78(1 H,m), 6. 60-7.00(2H,m), 7.20-7. 80(7H,m), 8.1 0-8.40(2H ! m),1 1 .8
(1H,br). mass:498(M+1)+.

Working Example No.303

40 [0687] The titled compound was obtained from the diastereomer of the compound of working example No.302.
H-NMR(DMSO-d 6 )

1 .25(1 H, m), 2. 00-2. 70(3H,m),2. 80-4.40(1 2H, m),4. 78(1 H,m), 6.75(1 H,s), 6. 98(1 H,d,J=5.4Hz), 7.20-7. 70(7H,m), 8.10
(1 H,d,J=5.4Hz),8.28(1 H,d,J=7.9Hz), 1 1 .8(1 H,br).
mass : 498(M+1)+.

45

Working Example No.304

[0688] According to the procedure described in the working example No.303, the compound of the working example
No.301 was used to afford the titled compound.
50 mass:498(M+1) + .

Working Example No.305

[0689]

55

(1) A mixture of the compound (50 mg) of the working example No. 293(4), isoprene (34 mg) and toluene (3 ml)
was reacted in a sealed tube at 1 20°C overnight. The reaction mixture was concentrated to afford a residue, which
was purified by TLC (Merck Art5744, chloroform-methanol (9:1) to afford adduct (52 mg).

187

EP 1 199 306 A1

(2) The compound obtained above in (1) was subjected to the reaction described in the working example No. 293
(5), to afford the titled compound (1 8 mg) as a white solid.

1 H-NMR(DMSO-d 6 )

1 .03(3H,t,J=7.3Hz),1 .25(1 H,m), 1 .68(s),1 .72(s),1 .68-1 .72(3H), 2.00-3. 20(9H,m), 3.42(1 H,m),3.78(1 H,m), 3.98(2H,
5 q,J=7.3Hz),4.80(1 H,dd,J=5.6,11 Hz), 5. 49(1 H,m). 6. 84(2H,m), 7.46(1 H,d,J=7.9Hz),7.55(1 H,d,J=7.9Hz),8.1 0(1 H,d,

J=5.2Hz),8.40(1H,d,J=7.9Hz),9.25(1H,s),1 2.0(1 H,br).
mass:475(M+1)+.

Working Example No.306

10

[0690]

(1) According to the procedure described in the working example No. 261 , the compound of the working example
No. 3 and 4-nitrobenzoyl chloride were used to afford a yellow solid.
15 (2) The compound (22.1 g) obtained above in (1) was subjected to the optical resolution by HPLC (CHIRALPAK

AD, hexane-ethanol(1 :1-1 :4) to afford the compound (A) (11 .2 g) at Rt=22 min and the compound (B) (10.1 g) at
Rt=30 min.

(3) A mixture of the compound (1 0 g) of (2)-A, 6N hydrochloric acid(30 ml) and acetic acid (30 ml) was stirred for
3 days at 80°C. The reaction mixture was cooled to room temperature and made alkaline by adding aqueous

20 saturated sodium bicarbonate solution. The mixture was extracted with chloroform.

The organic layer was washed with 1N potassium hydroxide solution and saturated brine and then dried over
magnesium sulfate. After filtration, the filtrate was concentrated to afford a residue, which was purified by column
chromatography on silica gel (Wakogel C-200, chloroform-methanol (1 00:0-98:2)) followed by the recrystallization
from ethanol to afford a white solid (3.1 g, 98%ee).

25 (4) According to the procedure described in the working example No. 80, the compound obtained above in (3) was

used to afford a white solid.

(5) According to the procedure described in the working example No. 84, the compound obtained above in (4) was

used - to afford a white solid, which is the optical isomer of the working example No. 91 .

mass:429(M+1)+.

30

Working Example No.307

[0691] According to the procedures described in the working example No. 306(3) to (5), the compound of the working
example No. 306(2)-B was used to afford the titled compound as a white solid.
35 mass:429(M+1)+.

Working Example No.308

[0692] According to the procedure described in the working example No.306, the compound of the working example
40 No.308 was prepared.
mass:429(M+1)+.

Working Example No.309

45 [0693] According to the procedure described in the working example No.307, the compound of the working example
No.309 was prepared,
mass : 429 (M+1) + .

Working Example No.31 0

50

[0694] According to the procedure described in the working example No.307, the compound of the working example

No.31 0 was prepared.

mass:469(M+1)+.

55 Working Example No.31 1

[0695] According to the procedure described in the working example No.306, the compound of the working example
No.31 1 was prepared.

188

EP 1 199 306 A1

mass:429(M+1) + .
Working Example No.312

5 [0696] According to the procedure described in the working example No. 307, the compound of the working example
No.312 was prepared.
mass:429(M+1)+.

Working Example No.313

10

[0697] According to the procedure described in the working example No. 290, the compound (51 mg) of the working

example No. 91 was used to afford the titled compound (12 mg) as a white solid.

mass:429(M+1)+.

15 Working Example No.314

[0698]

(1) A mixture of cyclopentanone (504 mg), pyrrolidine (498 mg), molecular sieves 4A (2 g) and toluene (30 ml)
20 was stirred overnight at room temperature. The reaction mixture was filtered through a celite pad and the filtrate

was concentrated to afford a residue, which was dissolved in chloroform (20 ml). To the solution, was added a
solution of ethyl 1 ,2,4-triazine-5- carboxylate in chloroform (1 0 ml). The mixture was stirred for 30 minutes at room
temperature and for 6 hours at 45°C. The reaction mixture was concentrated to afford a residue, which was purified
by column chromatography on silica gel (Wakogel C-200, hexane-ethyl acetate (4:1-1 :1)) to afford a yellow oily
25 compound (734 mg).

(2) According to the procedure described in the reference example No. 5, the compound (1 00 mg) obtained above
in (1) was used to afford the titled compound (101 mg) as a white solid.

1 H-NMR(DMSO-d 6 )

1.30(1H,m),2.14(2H ; quintet, J=7.5Hz),2.40(2H,m), 2.62(1 H,m),2 .92(4H,t,J=7.5Hz), 3.42(1 H,m), 3.75(1 H,m),
30 4.79(1 H,dd,J=5. 6,11 Hz), 6.68(1 H,s), 7.48(1 H,t,J=7.4Hz), 7.53(1 H,d,J=7. 4Hz), 7.66(1 H,s),8.03(1 H,s),8.33(1 H,d,

J=7.4Hz),12.1(1H,s).
mass:349(M+1)+.

Working Examples No.315-319

35

[0699] According to the procedure described in the working example No.314, the compounds of the working examples
No. 31 5 to No. 31 9 were prepared.

Working Example No.315

40

[0700] mass:377(M+1)+.
Working Example No.31 6
45 [0701] mass:378(M+1)+.
Working Example No.31 7
[0702] mass:454(M+1 )+.

50

Working Example No.31 8
[0703] mass:454(M+1 )+.
55 Working Example No.31 9
[0704] mass:450(M+1 ) + .

189

EP 1 199 306 A1

Working Example No.320

[0705] A mixture of the compound (100 mg) of the working example No. 319, 4N hydrochloric acid-dioxane (5 ml)
and methanol (3 ml) was stirred for 30 minutes at room temperature. To the reaction mixture, was added triethylamine.
5 The whole was concentrated to afford a residue, which was purified by column chromatography on silica gel (FL60D
FujiSilysia Co.), chloroform-methanol (100:0-95:5) to afford a white solid (72 mg).
mass:350(M+1)+.

Working Example No.321

10

[0706] According to the procedure described in the working example No. 84(2), the compound (17 mg) of the working

example No.320 and cyclopentanone (12 mg) were used to afford the titled compound.

mass:418(M+1)+.

is Working Example No.322

[0707] According to the procedure described in the working example No.321 , the compound of the working example

No.322 was prepared.

mass:364(M+1)+

20

Working Example No.323
[0708]

25 (1) According to the procedure described in the reference example No. 8, the compound of the working example

No.164(2)-A was used to afford the desired compound.

(2) According to the procedure described in the working example No. 133(2), the compound obtained above in (1)

was used to afford the hydrochloride of the titled compound.

1 H-NMR(DMSO-d 6 )

30 1 .00-1 .23(1 H, m), 2. 20-2. 90(7H,m), 3.40-3. 61 (2H,m),4.81 (1 H,m),6.90-7.51 (4H,m),8.08-8.37(2H ! m),9.95(1 H,brs),

11.4(1H,brs).
mass:352(M+1)+.

Working Example No.324

35

[0709] According to the procedure described in the working example No.323, the compound of the working example

No.1 64(2)-B was used to afford the hydrochloride of the titled compound.

mass:352(M+1)+.

40 Working Example No.325

[0710] According to the procedure described in the working example No. 133(2), the compound of the working ex-
ample No.1 64(2)-A was used to afford the titled compound.
1 H-NMR(DMSO-d 6 )

45 1 .00-1.21(1H,m),2.25-2.79(5H ! m),3.21-3.72(4H,m),4.65-4.90(2H,m),6.90-7.52(4H,m),8.13-8.38(2H,m),9.85(1H,s),
11.4(1H,brs).
mass:353(M+1) + .

Working Example No.326

50

[0711] According to the procedure described in the working example No. 133(2), the compound of the working ex-
ample No.1 64(2)-B was used to afford the titled compound.
mass:353(M+1)+.

190

EP 1 199 306 A1

Working Example No.327
[0712]

5 (1) According to the procedure described in the working example No. 96(1 ), the compound of the working example

No. 323(1) was used to afford the desired compound.

(2) According to the procedure described in the working example No. 133(2), the compound obtained above in (1)

was used to afford the titled compound.

lH-NMR(DMSO-d 6 )

10 1 .01-1 .20(1 H,m),2.22-2.78(5H,m),3.08-3.20(2H,m),3.32(1 H,m),3.55(1 H,m),4.81 (1 H,m),6.85-7.52(4H,m),

7.92-8.40(7H,m),9.90(1 H,s),11 .2(1 H,brs).
mass:538(M+1)+.

Working Example No.328

15

[0713]

(1 )According to the procedure described in the working example No. 323(1 ), the compound of the working example
No.164(2)-B was used to afford the desired compound.
20 (2)According to the procedure described in the working example No.327, the compound obtained above in (1 ) was

used to afford the titled compound.
mass:538(M+1) + .

Working Example No.329

25

[0714] Accordingto the procedures described in the working example No. 96(2) and (3), the compound of the working
example No. 327(1) and 1 -butanol were used to afford the hydrochloride of the titled compound.
1 H-NMR(DMSO-d 6 )

0.89(3H,t,J=7.8Hz),1 .01 -1 .1 7(1 H,m),1 .25-1 .41 (2H,m),1 .52-1 .64(2H,m), 2.26-2. 40(2H,m),2.52-2. 63(1 H,m),2.85-3.00
30 (4H,m),3.08-3.23(2H,m),3.26-3.35(1 H, m),3. 50-3. 60(1 H,m), 4. 80-4.86(1 H,m) ; 7.03(1 H,d,J=4.3Hz),7.26-7.35(2H,m),
7.56(1 H,t,J=7.8Hz),8.26-8.30(2H,m),8.81 (2H,m),1 0.3(1 H,s),1 1 .0(1 H,brs).
mass:408(M+1)+.

Working Example No.330

35

[0715]

(1) According to the procedure described in the working example No. 327(1), thecompound of the working example
No. 328(1) was used to afford the desired compound.
40 (2) According to the procedure described in the working example No.329, the compound obtained above in (1)

was used to afford the hydrochloride of the titled compound.
mass:408(M+1) + .

Working Example No.331

45

[0716] According to the procedure described in the working example No. 334, the compound of the reference example
No. 8 and (R)-3-(tert-butoxycarbonylamino)-1 .4-dimethanesulfonyloxybutane were used to afford the hydrochloride of
the titled compound.
1 H-NMR(DMSO-d 6 )

50 1 .05(1 H, m), 2. 00-2. 75(5H, m),3. 05-4. 95(1 1H,m), 7.1 2-7. 52(4H,m), 8.21 -8. 80(4H,m),1 0.5-11 .8(4H,m).
Working Example No.332

[0717] A mixture of the compound (1 5 ring) of the working example No. 331 , acetyl chloride (24 triethylamine (92
55 uj) and dimethylformamide (0.5 ml) was stirred for 5 minutes at room temperature. The reaction mixture was concen-
trated to afford a residue, which was purified by TLC (Merck Art5713, chloroform-methanol (1 9:1)) to afford the titled
compound (11 mg) as a light yellow solid.
1 H-NMR(CD 3 OD)

191

EP 1 199 306 A1

1 .10-1 .30(1 H,m),1 .65(1 H,m),1 ,90(3H,s),2.22(1 H,m),2. 40-2. 92(1 1 H,im),3.45(1 H,m),3.65(1 H,m),4.29(1 H,m),4.86(1 H,

m),6.8 7-7.00(2H,m),7.39-7.52(2H,m),8.14-8.30(2H,m).

mass:463(M+1)+.

5 Working Example No.333

[0718] According to the procedure described in the working example No. 96(1), the compound (20 mg) of the working

example No. 331 was used to afford the titled compound (1 6 mg) as a light yellow solid.

lH-NMR(DMSO-d 6 )

10 1 .12(1H,m),1 .45(1H,m),1 .89(1 H,m), 2. 20-2.75(1 OH, m), 3. 25-3. 75(4H,m), 4. 75-4.85(1 H,m), 6. 87-7. 50(4H,m), 8. 00-8.43
(6H,m).

Working Example No.334
15 [0719]

(1) A mixture of the compound (100 mg) of the working example No. 323(1), (S)-3-(tert-butoxycarbonylamino)-
1 ,4-dimethanesulfonyloxybutane (34 mg), N,N-diisopropyl ethylamine(46 mg) and dimethylformamide (1 ml) was
stirred for 1 hour at 80°C. The reaction mixture was cooled to room temperature and diluted with chloroform. The

20 whole was washed with aqueous saturated sodium bicarbonate solution and brine, and then dried over magnesium

sulfate. After filtration, the filtrate was concentrated to afford a residue, which was purified by column chromatog-
raphy on silica gel (Wakogel C-200, chloroform-methanol (1 :0-4:1)) to afford an ester (90 mg).

(2) According to the procedure described in the working example No. 133(2), the compound (100 mg) obtained
above in (1 ) was used to afford the hydrochloride of the titled compound (50 mg) as a white solid.

25 1 H-NMR(DMSO-d 6 )

1. 05(1 H, m),2. 00-2. 75(5H, m), 3. 05-4. 95(1 1H,m), 7.1 2-7. 52(4H,m), 8.21 -8. 80(4H,m),1 0.5-11 .8(4H,m).
mass:421(M+1) + .

Working Example No.335

30

[0720] According to the procedure described in the reference example No. 8, the compound of the working example
No.1 64(2)-B was used to afford the compound, which was subjected to the reaction described in the working example
No.334 to afford the hydrochloride of the titled compound,
mass : 421(M+1)+.

35

Working Example No.336
[0721]

40 (1 ) A solution of 2-(N-(tert-butoxycarbonyl)amino) -4-methylpyridine (2.26 g) in tetrahydrofuran (1 00 ml) was cooled

to -78°C. A solution of n-butyllithium in hexane (1 .5 M, 1 8.2 ml) was added and then warmed up to room temper-
ature. The reaction mixture was cooled again to -78°C, to which n-butylaldehyde (1 .48 ml) was added dropwise
and the whole was warmed up to room temperature. To the reaction mixture was added water and then extracted
with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. After

45 filtration, the filtrate was concentrated to afford a residue, which was purified by column chromatography on silica

gel (Wakogel C-300, hexane-ethyl acetate (1:0-1 :1)) to afford a white solid compound (1.37 g).

(2) According to the procedure described in the reference example No. 8(1 ), the compound (1 .00 g) obtained above
in (1) was used to afford the desired compound (700 mg).

(3) A mixture of the compound (700 mg) obtained above in (2), triphenylphosphine (700 mg), water (2 ml) and
50 tetrahydrofuran (30 ml) was stirred for 30 minutes. To the reaction mixture was added toluene and methanol at

room temperature. The whole was concentrated to afford a residue, which was purified by column chromatography
on silica gel (Wakogel C-300, chloroform- methanol(1 :0-4:1)to afford the desired compound (600 mg).

(4) According to the procedure described in the working example No. 96(1), the compound obtained above in (3)
was used to afford the desired compound.

55 (5)According to the procedure described in the working example No. 96(2), the compound (1 00 mg) obtained above

in (4) and ethanol were used to afford the desired compound (105 mg).

(6)According to the procedure described in the working example No.1 1 8(2), the compound (53 mg) obtained above
in (5) was used to afford the urea compound (40 mg), which was resolved by HPLC (CHIRALPAK AD) to afford

192

EP 1 199 306 A1

compound A (1 9 mg) and compound B (1 9 mg) in earler order of Rt.

(7)According to the procedure described in the working example No. 96(3), the compound (20 mg) obtained above

in (6)-A was used to afford the colorless oily compound (3.8 mg).

1 H-NMR(DMSO-d 6 )

5 0.70-1 .42(1 1 H,m),2.1 0-2.82(8H,m),3.05-3.81 (2H, m), 4.37-4. 88(1 H,m),6. 90-6. 97(1 H,m), 7.1 0(1 H,s),7. 28-7.51 (2H,

m) ! 8.15-8.37(2H ! m) ! 9.88(1H ! s) ! 11 .8(1 H,s).
mass:422(M+1)+.

Working Example No.337

10

[0722] According to the procedure described in the working example No. 96(3), the compound of the working example

No.336(6)-B was used to afford the titled compound (5.7 mg) as a colorless oil.

mass:422(M+1)+.

is Working Example No.338

[0723]

(1) According to the procedure described in the working example No. 84(2), the compound of the reference example
20 No. 8 and 2,4-dimethoxybenzaldehyde were used to afford the desired compound.

(2) According to the procedure described in the working example No. 96(1), the compound obtained above in (1)
and 1 -propansulfonylchloride were used to afford the desired compound.

(3) A solution of the compound obtained above in (2) in trifluoroacetic acid was stirred for 15 minutes at room
temperature. The reaction mixture was concentrated to afford a residue. The residue was crystallized from ether-

25 methanol to afford the title compound.

mass:458(M+1) + .

Working Example No.339

30 [0724] According to the procedure described in the working example No.1 40, the compound of the working example
No.339 was used to afford the titled compound,
mass : 472 (M+1)+.

Working Example No.340

35

[0725] According to the procedure described in the working example No.1 38, the compound of the working example

No.340 was used to afford the titled compound.

mass:458(M+1)+.

40 Working Example No.341

[0726]

(1) According to the procedure described in the reference example No.10, o-anisidine was used to afford the
45 desired compound.

(2) The compound obtained above in (1 ) was subjected to the procedure described in the reference example No.
1 1 to afford a crude product, which was dissolved in methanol and treated with 1 N hydrochloric acid. The reaction
mixture was filtered through a celite pad, and concentrated to afford a residue, which was solidified from ether-
methanol to afford the titled compound as a white solid.

50 mass:458(M+1)+.

Working Examples No.342-360

[0727] According to the procedure described in the working example No.341 , the compounds of the working examples
55 from No. 342 to No. 360 were prepared.

193

EP 1 199 306 A1

Working Example No.342
[0728] mass:458(M+1 )+.
5 Working Example No.343
[0729] mass:419(M+1)+.
Working Example No.344

10

[0730] mass:472(M+1)+.
Working Example No.345
15 [0731] mass:485(M+1)+
Working Example No.346
[0732] mass:510(M+1)+.

20

Working Example No.347
[0733] mass:435(M+1 )+.
25 Working Example No.348
[0734] mass:436(M+1 ) + .
Working Example No.349

30

[0735] mass:479(M+1)+.
Working Example No.350
35 [0736] mass:428(M+1)+
Working Example No.351
[0737] 1 H-NMR(DMSO-d 6 )

40 1 .07(1 H,m), 2.25-2. 35(2H,m),2. 58(1 H,m),2.93(2H,t,J=6.9Hz), 3.29(1 H ,m),3.53(1 H,m),3.86(2H,t,J=6.9Hz),4.82(1 H,
dd,J=5.6,1 1 Hz), 6. 90(1 H,d,J=5.5Hz),7.08(1 H,s),7.32(1 H,d,J=7.6Hz),7.46( 1 H,t,J=7.6Hz),7.97(2H,d,J=8.9Hz),8.1 7
(1 H,s),8.21 (1 H,d,J=5.5 Hz), 8. 26(1 H,d,J=7.6Hz),8.35(2H,d,J=8.9Hz),1 0.3(1 H,br),1 1 .0( 1 H,br), 13.0(1 H,br).
mass:620(M+1)+.

45 Working Example No.352

[0738] mass:430(M+1 ) + .

Working Example No.353

50

[0739] mass: 429(M-M) + .
Working Example No.354
55 [0740] mass:429(M+1)+.

194

EP 1 199 306 A1

Working Example No.355
[0741] mass:429(M+1)+.
5 Working Example No.356
[0742] mass:479(M+1 )+.
Working Example No.357

10

[0743] mass:430(M+1)+.
Working Example No.358
15 [0744] mass:468 (M+1)+
Working Example No.359
[0745] mass:479(M+1 )+.

20

Working Example No.360
[0746] mass:430(M+1 )+.
25 Working Example No.361
[0747]

(1) 6-Aminoquinoline was subjected to the reaction described in the reference examples No.1 0 and No. 11 to afford
30 sulfide as a by-product.

(2) According to the procedure described in the working example No. 133(2), the compound (64 mg) obtained
above in (1 ) was used to afford the titled compound (21 mg) as a white solid.

mass:445(M+1) + .

35 Working Example No.362
[0748]

(1) 6-Aminoquinoline was subjected to the reaction described in the reference examples No.1 0 and No. 11 to afford
40 chloride as a by-product.

(2) According to the procedure described in the working example No. 133(2), the compound (26 mg) obtained
above in (1 ) was used to afford the titled compound (1 8 mg) as a white solid.

mass:371(M+1)+.

45 Working Examples No.363-364

[0749] According to the procedure described in the working example No. 341 , the compounds of the working examples
from No. 363 to No. 364 were prepared.

50 Working Example No.363

[0750] mass:479(M+1 )+.

Working Example No.364

55

[0751] mass:418(M+1)+.

195

EP 1 199 306 A1

Working Example No.365
[0752]

5 (1) According to the procedure described in the working example No. 1 37(1 ), tert-butyldiphenylsilylether of 4-hy-

droxybenzaldehyde was used to afford the desired compound.

(2) According to the procedure described in the working example No. 139, the compound obtained above in (1)

was used to afford the hydrochloride of the titled compound as a white solid.

lH-NMR(DMSO-d 6 )

10 1 .07-1 .1 6(1 H,m),2.26-2.61 (3H, m), 2. 80(3H,s),2.83(3H,s),3. 00-3. 1 7(3H ,m),3.25-3. 34(1 H,m), 3.45-3. 56(3H,m),

4.11(2H 5 t ) J=4.2Hz) ) 4.36(2H ) t ) J=4.3Hz),4.82(2H 5 dd 5 J=6.2,12Hz ), 6.97-7.07(3H,m),7.25-7.54(5H,m) ; 8.23-8.28

(2H,m), 9.37(2H,br),1 0.2(1 H,br),1 0.4(1 H,br),1 0.9(1 H,br).

mass:529(M+1) + .

is Working Examples No.366-375

[0753] According to the procedure described in the working example No.365, the compounds of the working examples
from No. 366 to No. 375 were prepared.

20 Working Example No.366

[0754] mass:549(M+1 ) + .

Working Example No.367

25

[0755] mass:555(M+1)+
Working Example No.368
30 [0756] mass:569(M+1)+.
Working Example No.369
[0757] mass:571 (M+1 )+.

35

Working Example No.370
[0758] mass:549(M+1 ) + .
40 Working Example No.371
[0759] mass:577(M+1 ) + .
Working Example No.372

45

[0760] mass:549(M+1)+.
Working Example No.373
50 [0761] mass:577(M+1) + .
Working Example No.374
[0762] mass:583(M+1 )+.

55

Working Example No.375
[0763] mass:585(M+1 )+.

196

EP 1 199 306 A1

Working Example No.376
[0764]

5 (1) To a solution of 2-pyridinecarboxyaldehyde (51 0 mg) in benzene (20 ml) was added methyl triphenylphospho-

ranylidene acetate(1.7 g). The mixture was stirred for 2 hours at room temperature. The reaction mixture was
concentrated to leave a residue, which was purified by column chromatography on silica gel (Wakogel C-300,
hexane-ethyl acetate (4:1-3:1) to afford the desired compound (621 mg).

(2) According to the procedure described in the working example No. 297, the compound (621 mg) obtained above
10 in (1) was used to afford the desired compound (252 mg).

(3) According to the procedure described in the working example No. 365, the compound (20 mg) obtained above
in (2) was used to afford the hydrochloride of the titled compound (24 mg) as a yellow solid.
1 H-NMR(CD 3 OD)

1 .1 3(1 H,m),2.42(2H ; m),2.70(1 H,m),3.60-3.82(2H,m),3.37-3.47(3H,m),4.03(1 H,m) ; 4.20-4.38(3H,m),4.96(2H,m),
15 6.81-8.72(16H,m).

Working Example No.377

[0765]

20

(1) According to the procedure described in the working example No. 137(1), tert-butyldiphenylsilylether of 3-hy-
droxybenzaldehyde was used to afford the desired compound.

(2) According to the procedure described in the working example No. 139, the compound obtained above in (1)
was used to afford the hydrochloride of the titled compound as a white solid.

25 1 H-NMR(DMSO-d 6 )

1 .04(1 H,m),2.23-2.34(2H,m),2.70(1 H,m),3. 07-3. 20(4H,m),3. 28(1 H,m),3.51 (1 H,m) ; 4.1 6(2H,m), 4.84(1 H,dd,J=6.
4,10Hz),5.39(2H,s),7.08-7.20(2H,m),7.28-7.39(4H,m),7.43-7.52(2H,m),7.71(1H ) m),7.86(1H,d,J=8.6Hz),
8.20-8.28(2H,m),8.77(1H,m),9.64(2H,br),10.7(1H,br),11.1(1H,br).
mass: 549 (M-i-1) + .

30

Working Examples No.378-387

[0766] According to the procedure described in the working example No.377, the compounds of the working examples
from No. 378 to No. 387 were prepared.

35

Working Example No.378
[0767] mass:549(M+1 )+.
40 Working Example No.379
[0768] mass:549(M+1 ) + .
Working Example No.380

45

[0769] mass:577(M+1)+.
Working Example No.381
50 [0770] mass:577(M+1) + .
Working Example No.382
[0771 ] m as s : 52 9 ( M + 1 ) + .

55

Working Example No.383
[0772] mass:585(M+1 )+.

197

EP 1 199 306 A1

Working Example No.384
[0773] mass:571 (M+1 )+.
5 Working Example No.385
[0774] mass:555(M+1 )+.
Working Example No.386

10

[0775] mass:569(M+1)+.
Working Example No.387
15 [0776] mass:583(M+1)+.
Working Example No.388

[0777] According to the procedure described in the reference example No. 3, the compound (1 9 mg) of the working
20 example No. 376 was used to afford the titled compound (14 mg).
1 H-NMR(CD 3 OD)

1 .1 2(1 H,m), 2.24-2. 41 (3H,m),2. 70(1 H,m),3.32-3. 41 (4H,m),3. 55-3. 75(2H,m), 4. 02-4.32(5H,m) ! 4.92(3H,m),6.88(2H,
m),7.22(2H,m), 7.30(1 H,m),7.40-7.50(3H,m),7.89(1 H,m), 8. 03(2H,m), 8.22(1 H,m), 8.43(1 H,m),8.69(1 H,m).

25 Working Example No.389

[0778]

(1) A mixture of 6-amnionicotinicacid (1 .01 g), lithium aluminum hydride (835 mg) and tetrahydrofuran was refluxed
30 for 23 hours. The reaction mixture was cooled to room temperature and water (840 uJ), 1 N sodium hydroxide (840

[i 1 ) solution and water (840uJ) were added respectively. The whole was filtered through a celite pad and the filtrate
was concentrated to leave a residue, which was purified by column chromatography on silica gel (Wakogel C-200,
chloroform-methanol (50:1-10:1 ) to afford the desired compound (223 mg).

(2) A mixture of the compound (223 mg) obtained above in (1 ), tert-butyldimethylchlorosilane (332 mg), imidazole
35 (244 mg) and dimethylformamide (5 ml) was stirred for 30 minutes at room temperature. To the reaction mixture,

was added water and extracted with chloroform. The organic layer was washed with saturated brine and dried
over magnesium sulfate.

After filtration, the filtrate was concentrated to leave a residue which was purified by column chromatography on
silica gel (Wakogel C-200, hexane-ethyl acetate (3:2) to afford the desired compound (341 mg).
40 (3) According to the procedure described in the working example No. 11 8(2), the compound (320 mg) obtained

above in (2) was used to afford the desired compound (138 mg).

(4) A mixture of the compound (1 03 mg) obtained above in (3), acetic acid (1 ml), water (1 ml) and tetrahydrofuran
(1 ml) was stirred for 3 days at room temperature. The reaction mixture was concentrated to leave a residue, which
was purified by TLC (Merck Art5744, chloroform-methanol (1 0:1)) to afford the titled compound (44 mg) as a white
45 powder.

1 H-NMR(DMSO-d 6 )

1 . 07(1 H,m),2. 22-2. 57(3H,m), 3. 30(1 H,m),3.53(1 H,m), 4.46(2H,d,J=5.0Hz),4.82(1 H,dd,J=5.6,1 0Hz),5.23(1 H,t,
J=5.0Hz ) ; 7.25(1 H,d,J=8.6Hz),7.31 (1 H,dd,J=0.9,8.0Hz),7.46(1 H,t,J=8. 0Hz),7.73(1 H,dd,J=2.3,8.6Hz),8.23(1 H,
d,J=2.3Hz),8.31 (1 H,dd, J=0. 9, 8.0Hz), 9. 92(1 H,s),1 1 .2(1 H,br).
50 mass:339(M+1) + .

Working Example No.390

[0779] According to the procedure described in the working example No. 498, the compound of the working example
55 No.390 was used to afford the titled compound,
mass : 352 (M+1)+.

198

EP 1 199 306 A1

Working Example No.391
[0780]

5 (1) To a mixture of the compound (1 03 mg) of the working example No. 389, triethylamine (0.6 ml) and dimethyl-

sulfoxide (3 ml), was added a sulfur trioxide pyridine complex (265 mg). The mixture was stirred for 4 hours at
room temperature. To the reaction mixture, sulfur trioxide pyridine complex (195 mg) was added again and the
mixture was stirred for 1 hour at room temperature. The reaction mixture was diluted with chloroform and washed
with water and saturated brine and dried over magnesium sulfate. After filtration, the filtrate was concentrated to

10 afford a crude product, which was used in the next reaction without further purification.

(2)According to the procedure described in the working example No. 84(2), the compound (36 mg) obtained above in

(1 ) and a solution of ethylamine in methanol (2.0 M, 2 ml) were used to afford the titled compound (20 mg) as a white
powder.

1 H-NMR(DMSO-d 6 )

15 1.15(1H,m),1 .20(3H ) t,J=7.3Hz) ) 2.32-2.38(2H,m),2.53(1H,m),3.00(2H,q ) J=7.3Hz),3.30(1H,m) ! 3.55(1H,m),4.14(2H,

s),4.79(1 H,dd,J=5.6,1 0Hz),7.33(1 H,d,J=7.9Hz),7. 46(1 H,d,J=8.8Hz), 7.48(1 H,t,J=7.9Hz),7.88(1 H,dd,J=2.3,8.8Hz) ,
8.27(1 H,d,J=7.9Hz), 8.36(1 H,d,J=2.3Hz),1 0.1 (0.2H,s),1 0.6(0. 3H,br).
mass:366(M+1)+

20 Working Example No.392

[0781] According to the procedure described in the working example No.391 , the compound of the working example

No.392 was prepared.

mass:380(M+1)+.

25

Working Example No.393
[0782]

30 (1) According to the procedure described in the working example No.118(2), 2-amino-5-nitropyridine (139 mg) was

used to afford the desired compound. (33 mg).

(2) According to the procedure described in the reference example No. 3, the compound (33 mg) obtained above
in (1) was used to afford the desired compound (26 mg) as a white powder.

1 H-NMR(DMSO-d 6 )

35 1 .12(1H,m),2.31-2.45(3H,m),2.55(1H,m),3.53(1H,m), 4.77(1 H,dd,J=4. 5,1 0Hz),5.05(2H,s), 6. 99(1 H,m), 7.07(1 H,

dd,J=3.1, 8.8Hz), 7.27(1 H,d,J=7.8Hz), 7.43(1 H,t,J=7.8Hz), 7.67(1 H,d,J=3.1 Hz), 8.32(1 H,d,J=7.8Hz), 9.47(1 H,s).
mass:324(M+1) + .

Working Example No.394

40

[0783]

(1) According to the procedure described in the working example No.118(2), 2-amino-5-bromopyridine (643 mg)
was used to afford the desired compound (989 mg).
^5 (2) According to the procedure described in the reference example No. 6, the compound (218 mg) obtained above

in (1) was used to afford the desired compound (150 mg).

(3) A mixture of the compound (30 mg) obtained above in (2), 1 -methylpiperazine (1 0 (a I), tris(dibenzylidenacetone)
dipalladium(0)(3 mg), 1 ,1 -bis(diphenylphosphino)ferrocene (3 mg), 2,2-bis(diphenylphosphino)-1 ,1-binaphthyl (3
mg) and sodium tert-butoxide (9 mg) and tetrahydrofuran (2 ml) was reacted in a sealed tube for 2 hours at 1 00°C.

50 The reaction mixture was cooled to room temperature and filtered through silica gel and celite. The filtrate was

concentrated to leave a residue which was purified by TLC (Merck Art5744, chloroform-methanol (10:1)) to afford
the desired compound (1 7 mg).

(4) According to the procedure described in the working example No. 133(2), the compound (17 mg) obtained
above in (3) was used to afford the hydrochloride of the titled compound (1 5 mg) as a white solid.

55 1 H-NMR(DMSO-d 6 )

1. 04(1 H,m),2. 23-2. 38(2H,m), 2. 58(1 H,m),2.80(s),2. 81 (s),2. 80-2.81 (3H), 3. 06-3. 22(4H, 17^3.30(1 H,m), 3.48-3. 58
(3H,m),3.75-3.79(2H,m) ; 4.83(1 H,dd,J=5.6,1 0Hz), 7.30(1 H,dd,J=0. 9,8.1 Hz), 7 .36(1 Hbrd,J=9.2Hz),7.45(1 H,t,
J=8.1Hz),7.65(1H,dd,J=2.7,9.2H z), 7. 99(1 H,d,J=2.7Hz), 8.24(1 H,dd,J=0.9,8.1 Hz),1 0.1 (1 H,br),1 0.8(1 H,br).

199

EP 1 199 306 A1

mass:407(M+1) + .

Working Examples No.395-397

5 [0784] According to the procedure described in the working example No. 394, the compounds of the working examples
from No. 395 to No. 397 were prepared.

Working Example No.395

10 [0785] mass:366(M+1)+

Working Example No.396

[0786] mass:352(M+1 )+.

15

Working Example No.397
[0787] mass:338(M+1 )+.
20 Working Example No.398
[0788]

(1 ) 2-Amino-5-brornopyridine and tributylvinylthin were subjected to the reaction procedure described in the work-
25 jng example No.429(2) to afford the desired compound.

(2) According to the procedure described in the working example No.1 1 8(2), the compound (6 mg) obtained above
in (1) was used to afford the titled compound (2 mg) as a white solid.

1 H-NMR(DMSO-d 6 )

0.80-0.92(1 H,m), 2. 35-2. 50(2H,m), 2.55-2. 65(1 H, m),3. 02-3. 50(1 H,m),3. 72-3. 82(1 H, m), 4. 77-4.84(1 H,m), 5.35(1 H,
30 d,J=9.0Hz),5.73(1H,d,J=18Hz), 6.68(1 H,dd,J=9. 0,1 8Hz), 6. 72-7. 00(1 H,m), 7.45-7. 60(3H,m), 7.80(1 H,m), 8.1 7(1 H,

m), 8.27(1 H,d,J=7.0Hz), 11 .8(1 H,br).
mass:335(M+1)+.

Working Example No.399

35

[0789] According to the procedure described in the reference example No. 3, the compound (4 mg) of the working

example No.398 was used to afford the titled compound (3 mg) as a white solid.

1 H-NMR(DMSO-d 6 )

0.80-0.90(1 H,m), 1 .22(3H,t,J=7.4Hz),2.40-2.50(2H,m), 2.58-2 .65(1 H,m), 2.62(2H,q,J=7.4Hz), 3.42-3.50(1 H,m),
40 3.70-3.82(1 H,m), 4.80(1 H,m), 6. 70(1 H,d,J=9.0Hz) ; 7.46(1 H,t,J=7.0Hz) , 7.50-7. 60(2H,m), 8.04(1 H,d), 8.30(1 H,d,
J=7.4Hz), 11.9(1H,br).
mass:337(M+1) + .

Working Example No.400

45

[0790]

(1) To a mixture of methyl 2-acetoaminopyridine-4-carboxylate (19 mg), sodium periodate (7mg), iodine (12 mg),
water (25 llI) and acetic acid (0.12 ml), was added one drop of concentrated sulfuric acid. The mixture was stirred

50 for 23 hours at 85°C. To the reaction mixture was added aqueous sodium thiosulfate solution (5 ml). The mixture

was extracted with chloroform. The organic layer was dried over magnesium sulfate. After filtration, the filtrate was
concentrated to leave a residue, which was purified by TLC (Merck Art5 744, chloroform-methanol (20:1)) to afford
the desired compound (15 mg) as a yellow powder.

(2) The compound obtained above in (1) was subjected to the reaction described in the working example No.398
55 to afford the titled compound (2 mg) as a white solid.

1 H-NMR(DMSO-d 6 )

0.85-0.92(1 H, m), 2. 37-2. 47(2H,m), 2.55-2. 59(1 H, m),3.43-3. 51 (1H,m),3. 74-3. 81 (1H,m), 3. 97(3H ; s), 4.82(1 H,m),
5.43(1 H,d,J=1 0Hz), 5. 66(1 H,dd,J=1 .0,1 0Hz), 7. 22-7.32(1 H,m), 7.49(1 H,t,J=7.8Hz), 7.58(1 H,m),8. 05(1 H,s), 8. 26

200

EP 1 199 306 A1

(1 H,d,J=8.0Hz) ,8.43(1 H,s),11 .5(1 H,br).
mass:393(M+1) + .

Working Example No.401

5

[0791] According to the procedure described in the reference example No. 3, the compound (2 mg) of the working

example No. 400 was used to afford the titled compound (1 mg) as a white solid.

1 H-NMR(DMSO-d 6 )

0.70-0.80(1 H, m),1.25(3H,t,J=7.5Hz),2.30-2.50(2H,m), 2. 94(2H,q,J=7.5Hz),3.41 -3. 50(1 H,m),3. 74-3.82(1 H,m),3. 98
10 (3H,s),4.24-4.30(1 H,m),4.78-4.820(1 H,m),7.20(1 H ,s). 7.43-7. 60(2H,m), 7. 67-7. 76(1 H,m), 8.1 7(1 H,s), 8. 26(1 H,d,
J=7.2Hz),11.6(1H,br).
mass:395(M+1)+.

Working Example No.402

15

[0792] According to the procedure described in the working example No.1 1 8(2), 2-aminopyridine (86 mg) was used

to afford the titled compound (15 mg) as a light red solid.

1 H-NMR(DMSO-d 6 )

1 .1 7(1 H,m), 2.24-2. 40(2H,m),2. 52(1 H,m),3.30(1 H,m), 3.54(1 H, m), 4.87(1 H,dd ; J=5. 0,1 0Hz), 7.1 8(1 H,t,J=5.0Hz), 7.34
20 (1 H,dd,J=0. 9,7.8Hz), 7.49(1 H,tJ=7.8Hz), 8.30(1 H,dd,J=0. 9 , 7.8Hz), 8.71 (2H,d, J=5.0Hz), 1 0.4(1 H,s), 11 .6(1 H,s).
mass:310(M+1)+.

Working Example No.403

25 [0793]

(1) A mixture of 2-amino-4,6-dichloropyrimidine (1 .0 g). 1 -methylpiperazine (733 mg), triethylamine (1 .3 ml) and
1-butanol (15 ml) was stirred for 22 hours at 80°C. The reaction mixture was concentrated and then diluted with
chloroform-methanol (10:1). The whole was filtered through silica gel (Wakogel C-200). The filtrate was concen-

30 trated to afford a crude product.

(2) According to the procedure described in the reference example No. 3, a solution of the compound obtained
above in (1 ) in ethanol (1 8 ml) was used to afford the desired compound (390 mg).

(3) According to the procedure described in the working example No.1 1 8(2), the compound (74 mg) obtained above
in (2) was used to afford the titled compound (14 mg) as a white solid.

35 1 H-NMR(CDCI 3 )

I. 27(1 H,m), 2. 35(3H,m),2.34-2.60(7H,m), 3. 42(1 H,m),3. 64-3. 80(5H ; m), 4.76(1 H,dd,J=5. 3,11 Hz), 5.22(1 H,d,
J=6.4Hz), 7.36(1 H,s), 7.45(1 H,t,J=7.7Hz), 7.52(1 H ; dd,J=1 .1 ,7.7Hz) ; 7-94(1 H,d,J =6.4Hz), 8.26(1 H,dd,J=1 .1 ,7.7Hz),

II. 8(1H,s).
mass:408(M+1)+.

40

Working Examples No.404-405

[0794] According to the procedure described in the working example No. 406, the compounds of the working examples
from No. 404 to No. 405 were prepared.

45

Working Example No.404
[0795] mass:385(M+1 )+.
50 Working Example No.405
[0796] mass:359(M+1 )+.
Working Example No.406

55

[0797]

(1) According to the procedure described in the reference example No. 2, indole was used to afford the desired

201

EP 1 199 306 A1

compound.

(2) According to the procedure described in the working example No. 129, the compound obtained above in (1)

was used to afford the titled compound.

mass:355(M+1)+.

5

Working Example No.407

[0798] According to the procedure described in the working example No. 408, the titled compound was prepared.
mass:363(M+1)+.

10

Working Example No.408
[0799]

*s (l)According to the procedure described in the reference example No. 3, the compound of the working example

No. 406(1) was used to afford the desired compound.

(2)According to the procedure described in the working example No.1 , the compound obtained above in (1) was

used to afford the titled compound.

mass:357(M+1)+.

20

Working Example No.409
[0800]

25 (1) A mixture of 2-chloro-3-nitrobenzoic acid (3 g), diethyl aminomalonate hydrochloride (3.47 g), HOBT monohy-

drate (2,51 g), triethylamine (3.11 ml) and dimethylformamide (36 ml) was cooled in an ice-bath and WSC hydro-
chloride (3.37 g) was added. The reaction mixture was stirred for 3 hours at room temperature and diluted with
ethyl acetate (200 ml). The whole was washed with 1 N hydrochloric acid, aqueous saturated sodium bicarbonate
solution and saturated brine, and then dried over magnesium sulfate. After filtration, the filtrate was concentrated

30 to leave a crude solid, which was washed with ethyl acetate to afford the first crystal (2.49 g) and the second crystal

(0.895 g) was obtained from the mother liquid.

(2) The solution of first crystal (1 .50 g) obtained above in (1) in dimethylsulfoxide (30ml) was cooled in an ice-bath
and sodium hydride (230 mg) was added. The reaction mixture was stirred for 10 minutes at 90°C and aqueous
saturated ammonium chloride solution was added. The whole was diluted with ethyl acetate (1 50 ml). The organic

35 layer was separated. The organic layer was washed with water and saturated brine and then dried over magnesium

sulfate. After filtration, the filtrate was concentrated to leave a crude product (1 .36 g).

(3) A solution of the crude product (16.47 g) obtained above in (2) in ethanol (600 ml) was heated at 100°C and
1 N sodium hydroxide solution (52 ml) was added. The reaction mixture was stirred for 40 minutes and then cooled.
After filtration, the filtrate was concentrated to leave a residue, which was purified by column chromatography on

40 silica gel (Wakogel C-200, hexane-ethyl acetate (1 :1-3:5) to afford an ester (5.76 g).

(4) The compound (5.76 g) obtained above in (3) was suspended in methanol (90 ml) and then cooled in an ice-
bath. To the cooled mixture, was added sodium borohydride (3.61 g) in four portions. The mixture was stirred for
50 minutes and aqueous saturated ammonium chloride solution (2 ml) was added. After filtration, the solid obtained
was washed with methanol to afford a white powder (3.48 g).

45 (5) To a mixture of the compound (1.00 g) obtained above in (4), imidazole (650 mg) and dimethylformamide (16

ml), was added tert-butyldimethylchlorosilane (1 .50 g). The mixture was stirred for 85 minutes at room temperature
and then diluted with ethyl acetate (200 ml). The whole was washed with water and saturated brine and then dried
over magnesium sulfate. After filtration, the filtrate was concentrated to leave a crude product, which was used for
the next reaction without further purification.

50 (6) The whole crude product obtained above in (5) was dissolved in ethanol (100 ml) and then subjected to the

reaction described in the reference example No. 3. The crude crystal obtained was washed with ether-hexane to
afford an amine (1.13 g).

(7) According to the procedure described in the working example No.1 , the compound (1 .13 g) obtained above in
(6) and 2-pyridine carbonylazide(650 mg) were used to afford the desired compound (1 .48 g).
55 (8) To the solution the compound (1.48 g) obtained above in (7) in methanol (30 ml), was added concentrated

hydrochloric acid (4 ml). The mixture was stirred for 30 minutes at room temperature. The solid precipitated was
collected by filtration and washed with tetrahydrofuran to afford the titled compound (1.18 g).
1 H-NMR(DMSO-d 6 ) 3.62(1 H,dd,J=5.7Hz,11 Hz), 3. 94(1 H,dd,J=3.9Hz,1 1 Hz),4.75(1 H,m ),7.09(1 H,m),7.36(2H,m),

202

EP 1 199 306 A1

7.44(1 H,t,J=7.7Hz),7.85(1H,m),8.14( 1 H,d,J=7.7Hz), 8.31 (1 H,m), 8. 60(1 H,s),1 0.1 8(1 H,s),1 0.92(1 H,s).
mass:299(M+1)+.

Working Examples No.410-413

5

[0801] According to the procedure described in the working example No. 41 4, the compounds of the working examples
from No. 41 0 to No. 41 3 were prepared.

Working Example No.410

10

[0802] mass:313(M+1)+.
Working Example No.411
15 [0803] mass:327(M+1)+.
Working Example No.412
[0804] mass:341(M+1)+.

20

Working Example No.413
[0805] mass:355(M+1 )+.
25 Working Example No.414
[0806]

(1) The compound (26 mg) of the working example No. 409(6) was dissolved in dimethylformamide-tetrahydrofuran
30 (1:1) (1 nil) and sodium hydride (5 mg) and benzylbromide (12 were added. The mixture was stirred for 30

minutes at room temperature and then filtrated with silica gel. The silica gel was washed with hexane-ethyl acetate
(1:1). The filtrate and the washing were combined and then concentrated to afford the crude product, which was
used for the next reaction.

(2) According to the procedure described in the working example No.1, the compound obtained above in (1) and
35 2-pyridine carbonylazide were used to afford the desired compound.

(3) The compound obtained above in (2) was subjected to the similar reaction to that described in the working
example No. 409(8) to afford the titled compound (25 mg) as a light yellow powder.

1 H-NMR(DMSO-d 6 )

3.92-4.00(2H ) m) ) 4.34(1H ) d ! J=11Hz) ) 4.58(1H ) t ) J=4.5Hz) ! 5.20(1 H,d,J=11 Hz), 7.1 0(1 H,m),7.25-7.38(5H,m),7.43-
40 7.50(3H,m),7.86(1 Km), 8. 08(1 H, m), 8. 20(1 H,m),1 0.2(1 H,s),1 0.5 (1 H,s).

mass:389(M+1)+.

Working Examples No.41 5-423

45 [0807] According to the procedure described in the working example No.414, the compounds of the working examples
from No.41 5 to No. 423 were prepared.

Working Example No.41 5

50 [0808] mass:338(M+1) + .

Working Example No.41 6

[0809] mass:355(M+1 )+.

55

Working Example No.41 7
[0810] mass:369(M+1)+.

203

EP 1 199 306 A1

Working Example No.418
[0811] mass:375(M+1)+.
5 Working Example No.419
[0812] mass:403(M+1)+.
Working Example No.420

10

[0813] mass:409(M+1)+.
Working Example No.421
15 [0814] mass:395(M+1)+
Working Example No.422
[0815] mass:379(M+1)+.

20

Working Example No.423

[0816] mass:381(M+1)+.

25 Working Examples No.424-426

[0817] According to the procedure described in the working example No. 427, the compounds of the working examples
from No. 424 to No. 426 were prepared.

30 Working Example No.424

[0818] mass:297(M+1)+.

Working Example No.425

35

[0819] mass:311(M+1)+.
Working Example No.426
40 [0820] mass:339(M+1)+.
Working Example No.427
[0821]

45

(1) A mixture of the compound (11 mg) of the working example No. 414, triethylamine (40 uJ) and methanesulfo-
nylchloride (10 joJ) was stirred for 20 minutes at room temperature. To the reaction mixture, was added DBU (20
uJ). The mixture was stirred for 25 minutes at room temperature and further stirred for 14.5 hours at 80°C. The
reaction mixture was cooled to room temperature and filtrated with silica gel. The silica gel was washed with

50 hexane-ethyl acetate (1 :1). The filtrate and washing were combined and then concentrated to leave a residue,

which was purified by TLC (Merck Art5744, chloroform-methanol (20:1)) to afford the desired compound (6.4 mg).

(2) The compound obtained above in (1) was dissolved in ethanol-tetrahydrofuran and the mixture was subjected
to the similar reaction to that described in the reference example No. 3. The crude product obtained was purified
by TLC (Merck Art5744, chloroform-methanol (20:1) to afford the titled compound (3.8 mg).

55 1 H-NMR(DMSO-d 6 )

1.45(3H,d,J=6.6Hz),4.40(1H,d,J=16Hz), 4.55(1 H,q,J=6.6Hz),5.0 8(1 H,d,J=1 6Hz), 7.02(1 H,ddd,J=0. 9,5.1 ,7.2Hz),
7.24-7.39(6H,m), 7.42-7.51 (2H,m),7. 75(1 H,ddd,J=2.1 ,7.2,8. 7Hz), 8.1 3-8.1 7(2H,m), 9. 72(1 H,s),1 0.73(1 H,s).
mass:373(M+1)+.

204

EP 1 199 306 A1

Working Example No.428

[0822] According to the procedure described in the working example No. 427, the compound of the working example
No.428 was prepared.
5 mass:365(M+1)+.

Working Example No.429

[0823]

10

(1)A mixture of 2-chloro-3-nitrobenzoic acid (1 .49 g), concentrated sulfuric acid (50 and methanol (50 ml) was
ref luxed for 22 hours. The reaction mixture was diluted with chloroform and washed with water and saturated brine
and then dried over magnesium sulfate. After filtration, the filtrate was concentrated to afford a crude product (1 .56

g)-

15 (2)The compound (50 mg) obtained above in (1 ) and tetrakistriphenylphosphinepalladium (9 mg) were suspended

in tetrahydrofuran (1 ml). After degassing, tributyl(1 -ethoxyvinyl)tin (79 uJ) was added. The mixture was stirred for
1 hour at room temperature, for 2 hours at 50°C and further ref luxed for 2.5 hours. The reaction mixture was cooled
to room temperature and filtrated with silica gel. The silica gel was washed with hexane-ethyl acetate (3;1). The
filtrate and the washing were combined and concentrated to leave a residue, which was purified by TLC(Merck

20 Art5744, hexane-ethyl acetate (3:1) to afford the desired compound (53 mg) as a light yellow oil.

(3)To the compound (110 mg) obtained above in (2) in ethanol (2 ml) was added 1N sodium hydroxide solution
(437 (0,1). The reaction mixture was stirred for 17 hours at room temperature and then concentrated to leave a
residue. The residue was dissolved in water (4 ml) and washed with hexane. The aqueous layer was concentrated
to afford the desired compound (95 mg).

25 (4)The compound (45 mg) obtained above in (3) and aniline (1 8 joJ) were subjected to the similar reaction to that

described in the working example No. 409(1 ) to afford the desired compound (45 mg).

(5) A mixture of the compound (45 mg) obtained above in (4), concentrated hydrochloric acid (20 (_il) and ethanol
(2 ml) was stirred for 50 minutes at room temperature. The reaction mixture was concentrated to leave a solid,
which was washed with chloroform-ethyl acetate (3:1 ). The washing was purified by TLC (Merck Art5744, hexane-

30 ethyl acetate (3:1) to afford the desired compound.

(6) A mixture of the compound obtained above in (5) and triethylsilane (30 uJ) in chloroform was cooled in an ice-
bath. To the mixture, was added borontrifluoride ether complex (23^il). The reaction mixture was stirred for 2 hours
and 45 minutes at room temperature. The reaction mixture was purified by TLC (Merck Art5744, hexane-ethyl
acetate (3:1) to afford the desired compound.

35 (7)The compound obtained above in (6) was dissolved in ethanol and then subjected to the similar reaction de-

scribed in the reference example No. 3.

(8)The compound (7 mg) obtained above in (7) and 2-pyridinecarbonylazide (12 mg) were subjected the reaction
described in the working example No.1. The crude product was purified by TLC (Merck Art5744, hexane-ethyl
acetate (1 :1) to afford the titled compound (4 mg).
40 1 H-NMR(DMSO-d 6 )

1.43(3H,d,J=6.6Hz), 5.60(1 H,q,J=6.6Hz), 7.05(1 H,m), 7.24-7. 33(2H,m), 7.46-7. 57(4H,m), 7.68-7.82(2H,m),

8.28-8.33(2H,m),9.92(1H,s),11 .3(1 H,s).

mass:359(M+1)+.

45 Working Example No.430

[0824] According to the procedure described in the working example No. 431 , the compound of the working example

No.430 was prepared.

mass:339(M+1)+.

50

Working Example No.431
[0825]

55 (9)The compound (12 mg) obtained above in (8) and diethyl acetal of propionaldehyde (1 00 were dissolved in

chloroform- tetrahydrofuran(1 :1) (2 ml) and borontrifluoride ether complex (40 [il) was added. The mixture was
stirred for 6 hours at 1 20°C. Diethyl acetal of propionaldehyde (50 |oJ) was added again. The reaction mixture was
stirred for 3 hours at 120°C. Diethyl acetal of propionaldehyde (200 uJ) was added again. The reaction mixture

205

EP 1 199 306 A1

was stirred for 2.5 hours at 120°C. The reaction mixture was purified by TLC (Merck Art5744, chloroform-methanol

(10:1)) to afford the titled compound (2.3 mg).

1 H-MMR(DMSO-d 6 )

0.98(3H,t,J=7.OHz),1 .75(2H,m),3.1 9(1 H,t,J=1 0Hz),4.49(1 H,t,J =1 0Hz),5.1 8(2H,m),7.05(1 H,m),7.35-7.58(3H,m),
5 7.78(1H,m), 8.29(2H,m),9.88(1H,s),10.8(1H,s).

mass:339(M+1)+.

Working Examples No.432-437

10 [0826] According to the procedure described in the working example No. 431 , the compounds of the working examples
from No. 432 to No. 437 were prepared.

Working Example No.432

15 [0827] mass:387(M+1)+.

Working Example No.433

[0828] mass:341(M+1)+.

20

Working Example No.434
[0829] mass:311(M+1)+.
25 Working Example No.435
[0830] mass:417(M+1) + .
Working Example No.436

30

[0831] mass:417(M+1)+.
Working Example No.437
35 [0832] mass:417(M+1)+.
Working Example No.438
[0833]

40

(1) According the procedure described in the working example No. 56, 3-nitrophthalimide (2.00 g) and ethanol (800
(0,1) were used to afford the desired compound (2.11 g).

(2) The compound (2.11 g) obtained above in (1) was dissolved in methanol-tetrahydrofuran (1:4) (50 ml) and
cooled to -15 °C. Sodium borohydride (360 mg) was added. The mixture was stirred for 1 hour and aqueous

^5 saturated ammonium chloride solution was added. The mixture was warmed to room temperature and water was

added. The whole was extracted with chloroform. The organic layer was dried over magnesium sulfate. After fil-
tration, the filtrate was concentrated to leave a solid, which was washed with hexaneto afford the desired compound
(1-134 g).

(3) The compound (1 20 mg) obtained above in (2) was subjected to the similar reaction to that described in refer-
so ence example No. 3 to afford the desired compound (70 mg).

(4) According to the procedure described in the working example No.1 , the compound (70 mg) obtained above in (3)
and 2-pyridinecarbonylazide (65 mg) were used to afford the titled compound (26 mg).

1 H-NMR(DMSO-d 6 )

1 .25(3H,t,J=7.2Hz),3.42(1 H,m),3.71 (1 H,m), 6.00(1 H,d,J=9.0Hz) , 6.63(1 H,d,J=9.0Hz),7.1 0(1 H,ddd,J=1 .0,5.0, 7.0Hz),
55 7.30(1 H,d, J=7.5Hz), 7.37(1 H,dd,J=1 .0, 7.0Hz), 7.54(1 H,t,J=7.5Hz), 7.82(1 H , ddd, J=2.1 , 7.0,7.5Hz), 8.36-8.39(2H,

m), 9.98(1 H,s), 11.7(1H,s). mass:313(M+1)+.

206

EP 1 199 306 A1

Working Example No.439

[0834] According to the procedure described in the working example No. 440, the compound of the working example
No.439 was prepared.
5 mass:327(M+1)+.

Working Example No.440

[0835] The compound in working example No. 438(1 3 mg) was dissolved in ethanol(2 ml_) and catalytic quantity of
10 p-toluensulfonic acid was added. The mixture was stirred at 90 °C for 1 hour. The mixture was concentrated. The solid
yielded was recrystallized with hexane-ethyl acetate to afford the titled compound(7.3 mg).
1 H-NMR(DMSO-d 6 )

1 .01(3H,t,J=6.9Hz),1.20(3H,t,J=7,1Hz),2.85(1H,m),2.60(1H,m) ,3.25(1 H,m),3. 64(1 H,m), 6.1 5(1 H.s), 7.04(1 H,dd,
J=5.4,6.6Hz),7 .21 (1 H,d,J=8.0Hz), 7.36(1 H,d,J=7.2Hz), 7.53(1 H,t,J=8.0Hz), 7.7 7(1 H,ddd, J=2.1 , 6.6,7.2Hz), 8.28(1 H,
15 dd, J=2.7, 5.4Hz), 8.36(1 H,d ,J=8.0Hz), 9.97(1 H,s), 1 1 .8(1 H,s).
mass:341(M+1)+.

Working Examples No.441-448

20 [0836] According to the procedure described in the working example No.440, the compounds of the working examples
from No. 441 to No. 448 were prepared.

Working Example No.441

25 [0837] mass:355(M+1) + .

Working Example No.442

[0838] mass:369(M+1 )+.

30

Working Example No.443
[0839] mass:369(M+1 )+.
35 Working Example No.444
[0840] mass:383(M+1 ) + .
Working Example No.445

40

[0841] mass:367(M+1)+.
Working Example No.446
45 [0842] mass:395(M+1)+.
Working Example No.447
[0843] mass:381 (M+1 )+.

50

Working Example No.448
[0844] mass:403(M+1 )+.

55

207

EP 1 199 306 A1

Working Example No.449
[0845]

5 (1 ) According to the procedure described in the working example No. 56, 3-nitrophthalimide (2.02 g) and cyclopen-

tanol (1 .20 ml) were used to afford the desired compound (2.27 g).

(2) The compound (2.27 g) obtained above in (1 ) was subjected to the reaction described in the working example
No. 438(2) to afford the desired compound (1 .429 g).

(3) The compound (827 mg) obtained above in (2) was subjected to the reaction described in the working example
10 No. 440. The reaction mixture was concentrated to leave a crude product, which was used for the next reaction.

(4) The compound obtained above in (3) was subjected to the similar reaction to that described in the reference
example No. 3 to afford the desired compound (772 mg).

(5) According to the procedure described in the working example No.1 , the compound (772 mg) obtained above
in (4) and 2-pyridinecarbonylazide (600 mg) were used to afford the titled compound (448 mg).

15 1 H-NMR(DMSO-d 6 )

1 .52<8H,m>,2.81 <3H,s>,4.21 (1 H,m),6.24(1 H,s),7.04(1 H,ddd,J=1 .0,5.0,7.5Hz),7.23(1 H,dJ=7.5Hz),7.34(1 H,dd,
J=1 ,0 ; 7.0Hz),7. 52(1 H,t,J=7.5Hz),7.76(1 H,m),8.24(1 H ,m),8.34(1 H,m).9.95(1 H,s ),1 1 .6(1 H,s).
mass:335(M-MeOH)+.

20 Working Example No.450

[0846] The compound in working example No. 449(25 mg) was dissolved in ethanol and subjected to the reaction
described in the working example No. 440 to afford the titled compound(18 mg). 1 H-NMR(DMSO-d 6 )
0.99<3H,t,J=7.5Hz>,1 .55-2. 00<8H,m>,2. 78(1 H,m),3. 1 2(1 H,m), 4.22(1 H,m),6. 21 (1 H,s), 7.04(1 H,ddd,J=1 .0, 5.0,7.5Hz),
25 7.20(1 H, d,J=7.5Hz), 7.33(1 H,d,J=7.0Hz), 7.51 (1 H,t,J=7.5Hz),7. 77(1 H,m) ,8.27(1 H,m), 8.37(1 H,d,J=7.5Hz),9. 96(1 H,s),
11.8(1H,s).
mass:381(M+1) + .

Working Examples No.451-466

30

[0847] According to the procedure described in the working example No. 467, the compounds of the working examples
from No. 451 to No. 466 were prepared.

Working Example No.451

35

[0848] 1 H-NMR(DMSO-d 6 )

1 .55-1.99(14H,m),4.30(1H,m),4.45(2H,s) ) 7.03(1H,m) ; 7.32-7.50(3H,m),7.76(1H,m),8.15(1H,d,J=7.8Hz),8.28(1H,m) )

9.73(1H ,s), 10.7(1 H,br).

mass:379(M+1)+.

40

Working Example No.452
[0849] 1 H-NMR(DMSO-d 6 )

1 . 10-1. 70(1 2H,m),1 .95(1H,m),3.38(2H,d,J=7.8Hz),4.47(2H,s), 7.05(2H,m),7.33-7.51 (3H,m),7.78(1 H,m),8.08(1 H,d,
45 J=7.5Hz), 9.75(1H,s),10.8(1H,br).
mass:379(M+1)+.

Working Example No.453

50 [0850] 1 H-NMR(DMSO-d 6 )

1.1 0-1. 25(4H,m),1. 79-1 .92(4H ; m),2.1 0-2. 22(4H,m), 4.12(1H,m), 4.45(2H ; s), 7.05(1 H,m)7.33-7.57(3H,m), 7.78(1 H,
m), 8.18(1H,d,J=7.5Hz), 8.28(1 H,d1J=2.1 Hz), 9.69(1 H,s), 10.6(1H,br).

Working Example No.454

55

[0851] mass:419(M+1)+.

208

EP 1 199 306 A1

Working Example No.455
[0852] mass:419(M+1)+.
5 Working Example No.456
[0853] mass : 283 (M+1)+
Working Example No.457

10

[0854] mass:297(M+1)+.
Working Example No.458
15 [0855] mass:311(M+1)+.
Working Example No.459
[0856] mass:311(M+1)+.

20

Working Example No.460
[0857] mass:323(M+1 )+.
25 Working Example No.461
[0858] mass:337(M+1 ) + .
Working Example No.462

30

[0859] mass:327(M+1)+.

Working Example No.463

35 [0860] 1 H-NMR(DMSO-d 6 )

3.62(2H,t ) J=7.5Hz) ) 3.91(3H ) s) ; 4.34(2H ) t ) J=7.5Hz) ) 4.60(2H,s) , 7.02(1 Km), 7.38-7. 51 (3H,m), 7.99(1 H,m), 8.20(1 H,d,
J=7.8Hz), 8.39(1 H,d,J=2.1 Hz), 9.80(1 H,s), 11.0(1H,br).

Working Example No.464

40

[0861] mass: 331(M+1)+
Working Example No.465
45 [0862] mass:337(M+1)+.
Working Example No.466
[0863] mass:337(M+1 )+.

50

Working Example No.467
[0864]

55 (1)A mixture of the compound (20 mg) of the working example No. 449(2), 20% palladium hydroxide-carbon (20

mg), methanol (1 ml) and tetrahydrofuran (1 ml) was stirred for 1 5 hours at room temperature under an atmosphere
of hydrogen. The reaction mixture was filtered through a celite pad and the filtrate was concentrated to leave a
residue, which was purified by TLC (Merck A rt5 744, chloroform-methanol (19:1) to afford the desired compound

209

EP 1 199 306 A1

(5 mg).

(2)According to the procedure described in the working example No.1 , the compound (5 mg) obtained above in

(1) was used to afford the titled compound (2 mg) as a light yellow solid.

mass:337(M+1)+.

5

Working Example No.468

[0865] According to the procedure described in the working example No. 467, the compound of the working example
No.468 was prepared.
10 mass:339(M+1)+

Working Examples No.469-492

[0866] According to the procedure described in the working example No. 493, the compounds of the working examples
15 from No. 469 to No. 492 were prepared.

Working Example No.469

[0867] mass:365(M+1 )+.

20

Working Example No.470
[0868] mass:369(M+1 )+.
25 Working Example No.471
[0869] mass:387(M+1 ) + .
Working Example No.472

30

[0870] mass:401(M+1)+.
Working Example No.473
35 [0871] mass:407(M+1)+
Working Example No.474
[0872] mass:401 (M+1 )+.

40

Working Example No.475
[0873] mass:379(M+1 )+.
^5 Working Example No.476
[0874] mass:391 (M+1 ) + .
Working Example No.477

50

[0875] mass:325(M+1)+.
Working Example No.478
55 [0876] mass:339(M+1)+.

210

EP 1 199 306 A1

Working Example No.479
[0877] mass:353(M+1 )+.
5 Working Example No.480
[0878] mass:353(M+1 )+.
Working Example No.481

10

[0879] mass:401(M+1)+.
Working Example No.482
15 [0880] mass:339(M+1)+
Working Example No.483
[0881] mass:461(M+1)+.

20

Working Example No.484
[0882] mass:353(M+1 )+.
25 Working Example No.485
[0883] mass:367(M+1 ) + .
Working Example No.486

30

[0884] mass:367(M+1)+.
Working Example No.487
35 [0885] mass:367(M+1)+
Working Example No.488
[0886] mass:367(M+1 )+.

40

Working Example No.489
[0887] mass:367(M+1 )+.
45 Working Example No.490
[0888] mass:387(M+1 ) + .
Working Example No.491

50

[0889] mass:401(M+1)+.
Working Example No.492
55 [0890] mass:379(M+1)+.

211

EP 1 199 306 A1

Working Example No.493
[0891]

5 ("I) A solution of 3-nitrophthalic acid anhydride (125 g) in tetrahydrofuran (2.5 L) was cooled to -78 °C and sodium

borohydride (48.8 g) was added. The mixture was stirred for 1 hour and 1N hydrochloric acid was added. The
reaction mixture was warmed to room temperature and extracted with ethyl acetate. The organic layer was washed
with water and brine and then dried over magnesium sulfate. After filtration, the filtrate was concentrated to leave
a residue, which was purified by column chromatography on silica gel (Wakogel C-200, hexane-ethyl acetate (2:

10 1) to afford the desired compound (88.4 g).

(2) A mixture of the compound (200 mg) obtained above in (1 ), 3-amino-1 -propanol (90 mg), molecular sieves 3A
(500 mg) and tetrahydrofuran (3 ml) was refluxed overnight. The reaction mixture was filtered through a celite pad
and the filtrate was concentrated to leave a residue, which was purified by TLC(Merck Art5744, hexane-ethyl
acetate (1 :1) to afford the desired compound (180 mg).

*s (3) According to the procedure described in the reference example No. 3, the compound (1 80 mg) obtained above

in (2) was used to afford the desired compound (139 mg).

(4) According to the procedure described in the working example No.1 , the compound (30 mg) obtained above in

(3) was used to afford the titled compound (36 mg).
1 H-NMR(DMSO-d 6 )

20 1 .50-4.30(6H,m),5.86(1H,s),7.05(1H ; t,J=5.0Hz),

7.19(1H,d 5 J=8.0Hz),7.36(1H,d,J=6.0Hz),7.53(1H l t,J=8.0Hz),7. 78(1 H,t,J=8.0Hz),8.32(1 H,d,J=5.0Hz),8.38(1 H,d,

J=8.0Hz),9.99 (1H,s).

mass:325(M+1) + .

25 Working Examples No.494-502

[0892] According to the procedure described in the working example No.493, the compounds of the working examples
from No. 494 to No. 502 were prepared.

30 Working Example No.494

[0893] mass:339(M+1 )+.

Working Example No.495

35

[0894] mass:341(M+1)+.
Working Example No.496
40 [0895] mass:341(M+1)+.
Working Example No.497
[0896] mass:340(M+1 )+.

45

Working Example No.498
[0897] mass:325(M+1 )+.
50 Working Example No.499
[0898] mass:339(M+1 )+.
Working Example No.500

55

[0899] mass:387(M+1)+.

212

EP 1 199 306 A1

Working Example No.501
[0900] mass:399(M+1 )+.
5 Working Example No.502
[0901] mass:369(M+1)+.
Working Examples No.503-530

10

[0902] According to the procedure described in the working example No. 531 , the compounds of the working examples
from No. 503 to No. 530 were prepared.

Working Example No.503

15

[0903] mass:498(M+1)+.
Working Example No.504
20 [0904] mass:546(M+1)+.
Working Example No.505
[0905] mass:558(M+1 )+.

25

Working Example No.506
[0906] mass:528(M+1 )+.
30 Working Example No.507
[0907] mass:524(M+1 )+.
Working Example No.508

35

[0908] mass:528(M+1)+.
Working Example No.509
40 [0909] mass:546(M+1)+.
Working Example No.51 0
[0910] mass:560(M+1 )+.

45

Working Example No.51 1
[0911] mass:566(M+1)+.
50 Working Example No.51 2
[0912] mass:560(M+1 )+.
Working Example No.51 3

55

[0913] mass:538(M+1)+.

213

EP 1 199 306 A1

Working Example No.514
[0914] mass:550(M+1)+.
5 Working Example No.515
[0915] mass:484(M+1)+.
Working Example No.51 6

10

[0916] mass:560(M+1)+.
Working Example No.51 7
15 [0917] mass:498(M+1)+
Working Example No.51 8
[0918] mass:512(M+1)+.

20

Working Example No.51 9
[0919] mass:512(M+1)+.
25 Working Example No.520
[0920] mass:560(M+1 ) + .
Working Example No.521

30

[0921] mass:512(M+1)+.
Working Example No.522
35 [0922] mass:526(M+1)+
Working Example No.523
[0923] mass:526(M+1 )+.

40

Working Example No.524
[0924] mass: 526(M-M) + .
^5 Working Example No.525

[0925] mass: 526 (M+1) + ,
Working Example No.526

50

[0926] mass:526(M+1)+.
Working Example No.527
55 [0927] mass:546(M+1)+.

214

EP 1 199 306 A1

Working Example No.528
[0928] mass:560(M+1 )+.
5 Working Example No.529
[0929] mass : 538 (M+1)+
Working Example No.530

10

[0930] mass:599(M+1)+.
Working Example No.531
is [0931]

(1) A mixture of picolinic acid (150 g), dimethylformamide (20 ml) and thionylchloride (500 ml) was stirred for 1 hour
at 100 °C. The reaction mixture was cooled to 0 °C and methanol (200 ml) was added. The mixture was diluted
with ethyl acetate and saturated aqueous sodium bicarbonate was added. The organic layer was separated and

20 washed with water and brine, and then dried over magnesium sulfate. After filtration , the filtrate was concentrated

to leave a residue, which was purified by column chromatography on silica gel (Wakogel C-100, hexane-ethyl
acetate (2:1-1 :1 )) to afford the desired compound (1 48 g).

(2) The compound (18 g) obtained above in (1) andtributyl vinyltin (35 g) were subjected to the reaction described
in the working example No. 429(2) to afford the desired compound (1 6 g).

25 (3)According to the procedure described in the working example No. 300, the compound (1 6 g) obtained above in

(2) was used to afford the desired compound (1 9.7 g).

(4) According to the procedures described in the reference example No. 5(1) and (2), the compound (19.7 g) ob-
tained above in (3) was used to afford the titled compound (14.1 g).

1 H-NMR(CDCI 3 )

30 1 .85(1 H,m),2. 30-2. 90(5H,m), 3.48(1 H,quintet,J=7.0Hz), 3.68(2H,d,J=7.0Hz),7.20-7.40(5H,m), 7.45(1 H,d,

J=8.0Hz), 8.09(1 H,s),8.59(1 H,d,J=8.0Hz).

(5) According to the procedure described in the working example No.1 , the compound (50 mg) obtained above in
(4) and the compound (30 mg) of the working example No. 493(3) were used to afford the titled compound (41 mg).
1 H-NMR(CDCI 3 )

35 1 .60-4. 60(1 5H,m),5. 69(1 H,s), 6. 83(1 H,s),6. 91 (1 H,d,J=5.0Hz), 7.20-7.60(6H,m),8.13(1 H,d,J=5.0Hz),8.45(1 H,d,

J=5.0Hz), 8.77(1 H,s).
mass:484(M-i-1) + .

Working Example No.532

40

[0932] According to the procedure described in the working example No.531 , the compound of the working example

No.532 was prepared.

mass:498(M-i-1) + .

45 Working Example No.533

[0933]

(1) According to the procedures described in the working example No. 438(1) and (2), 3-nitrophthalimide(2.00 g)
50 in 4-hydroxy-2-butanone (1 .37 g) were used to afford the desired compound (1 .78 g).

(2) A mixture of the compound (1 ,78 g) obtained above in (1 ), molecular sieve 3A (5 g), and trifluoroacetic acid (1
ml) in tetrahydrofuran (25 ml) was stirred overnight at 1 00 °C. The reaction mixture was cooled to room temperature
and filtrated. The filtrate was concentrated to leave a residue, which was purified by column chromatography on
silica gel (Wakogel C-300, hexane-ethyl acetate (1 :1)) to afford the desired compound (963 mg).

55 (3)According to the procedure described in the reference example No. 3, the compound (963 mg) obtained above

in (2) was used to afford the desired compound (680 mg).

(4)According to the procedure described in the working example No. 1, the compound (30 mg) obtained above in

(3) was used to afford the titled compound (28 mg).

215

EP 1 199 306 A1

1 H-NMR(DMSO-d 6 )

1 .1 6(3H,d,J=7.0Hz),1 . 70-4. 30(5H,m),5. 95(1 H,s), 6. 90-8. 70(7H,m),1 0.0(1 H,s),1 1 .6(1 H,br).
mass:339(M+1) + .

5 Working Example No.534

[0934] mass:353(M+1 )+.

Working Example No.535

10

[0935] mass:339(M+1)+.
Working Example No.536
15 [0936] mass:353(M+1)+
Working Example No.537
[0937] mass:353(M+1 )+.

20

Working Example No.538
[0938] mass:367(M+1 )+.
25 Working Example No.539
[0939]

(1) A mixture of the compound (1 ,70 g) of the working example No. 493(3), (Boc) 2 0 (5.50 g), and 4-dimethylami-
30 nopyridine (3.00 g) in tetrahydrofuran (40 ml) was stirred overnight at room temperature. The reaction mixture was

concentrated to leave a residue, which was purified by column chromatography on silica gel (Wakogel C-300,
hexane-ethyl acetate (10:1-5:1)) to afford the desired compound (2.56 g).

(2) A solution of the compound (500 mg) obtained above in (1) in tetrahydrofuran (25 ml) was cooled to -78 °C
and butyliodide (400 j_il) and lithium hexamethyldisilazide in tetrahydrofuran (1.0 M, 3.6 ml) were added. The re-

35 action mixture was warmed up to room temperature slowly and saturated aqueous ammonium chloride was added.

The whole was extracted with ethyl acetate. The organic layer was washed with water and brine and then dried
over magnesium sulfate. After filtration, the filtrate was concentrated to leave a residue, which was purified by
column chromatography on silica gel (Wakogel C-300, hexane-ethyl acetate (1 0:1 )) to afford the desired compound
(484mg).

40 (3) A mixture of the compound (484 mg) obtained above in (2), trifluoroacetic acid (4 ml) and water (0.4 ml) was

stirred for 1 0 minutes at room temperature. The reaction mixture was concentrated to leave a residue, which was
purified by column chromatography on silica gel (Wakogel C-300, hexane-ethyl acetate (1 0:1 )) to afford the desired
compound (249 mg).

(4) According to the procedure described in the working example No.1 , the compound (50 mg) obtained above in
45 (3) was used to afford the titled compound (48 mg).

1 H-NMR(DMSO-d 6 )

0.61 (1 H,m),0.63(3H ! t,J=7.0Hz),1 .00-3.80(8H,m), 3.95(1 H,brd,J=11 Hz), 4.1 8(1 H,brd,J=1 1 Hz), 4.39(1 H,dt,
J=2. 0,11 Hz),7. 00-7. 20(2H,m), 7.37(1 H,d,J=7.0Hz),7.50(1 H,t,J=8.0Hz),7.78(1 H,t,J=8.0Hz),8. 23(1 H ; d,J=5.0Hz),
8.38(1 H,d,J=8.0Hz).1 0.0(1 H,s), 11 .8(1 H,br).
50 mass:381(M+1)+.

Working Example No.540

[0940] According to the procedure described in the working example No. 541 , the compound of the working example
55 No.540 was prepared.
mass:498(M-i-1) + .

216

EP 1 199 306 A1

Working Example No.541

[0941] According to the method in the working example No.1 , the titled compound (48 mg) was obtained using the
compound in working example No. 533(3) (30 mg) and the compound in working example No. 531 (4) (50 mg).
5 1 H-NMR(DMSO-d 6 )

1 .1 7(3H,d,J=7.0Hz),1 .20-2.90(1 0H,m),3.66(2H,s),4.21 (2H,m), 5.94(1 H,s)1 7.04(1 H,d,J=5.0Hz), 7.18(1 H,s), 7.20-7.40
(6H,m), 7.56(1 H,t,J=8.0Hz), 8.22(1 H,d,J=5.0Hz), 8.45(1 H,d,J=8.0Hz), 9. 96(1 H,s), 11 .7(1 H,br).
mass : 498(M+1) + .

fo Working Examples No.542-545

[0942] According to the procedure described in the working example No.541 , the compounds of the working examples
from No. 542 to No. 545 were prepared.

15 Working Example No.542

[0943] mass:512(M+1)+.

Working Example No.543

20

[0944] mass:512(M+1)+.
Working Example No.544
25 [0945] mass:512(M+1) + .
Working Example No.545
[0946] mass:526(M+1 )+.

30

Working Example No.546
[0947]

35 (l)According to the procedure described in working example No. 121 (1 ), the desired compound (9.00 g) was pre-

pared using 2-chloro-3-nitrobenzoic acid(10.1 g) and hydrazine monohydrate (4.85 mL).

(2)The compound (9.00 g) obtained above in (1) in ethanol(1 L) was sealed in sealed tube and stirred at 150 °C
for 15 hours. After the mixture was cooled to room tempeture, the precipitated crystal was filtrated and dried to
afford the desired compound (5.00 g).

40 (3) A mixture of the compound (40 mg) obtained above in (2). 1 ,4-butanediiodine (29 ^l) and dimethylformamide

(1 ml) was refluxed for 15 hours. The reaction mixture was cooled to room temperature and diluted with ethyl
acetate. The whole was washed with saturated aqueous sodium bicarbonate, water and brine, and then dried over
magnesium sulfate. After filtration, the filtrate was concentrated to leave a residue, which was purified by TLC
(Merck Art5744, hexane-ethyl acetate(1 :2)) to afford the desired compound (44 mg).

45 (4) According to the procedure described in reference example No. 3, the desired compound was afforded using

the compound (49 mg) obtained above in (3).

(5) According to the procedure described in working example No.1 , the titled compound was obtained as a white

solid using the compound (25 mg) afforded above in (4).

1 H-NMR(DMSO-d 6 )

50 1 . 65-1. 78(2H,m),1. 88-2. 11(2H ! m), 3. 39-3. 50(2H,m),3.80-3.96(2H,m), 7.00-7.1 3(1 H,m), 7. 20-7.39(2H,m) !

7.40-7.49(1 H ! m),7.75-7.85(1 H,m),8.1 5-8.22(1 H,m), 8.32(1 H,5),9.93(1 H,s),1 1 .1 (1 H,s).
mass:324 (M+1)+.

Working Example No.547

55

[0948] According to the methods described in working example No.546 from (3) to (5), the titled compound was
obtained as a white solid using the compound in working example No. 546(2) and 1 ,3-propandiiodine.
1 H-NMR(DMSO-d 6 )

217

EP 1 199 306 A1

2.49(2H,m),3.55-3.71 (2H,m),3.71 -3.81 (2H,m),7.01 -7.1 0(1 H,m),7.1 8-7.22(1 H,m), 7.28-7. 40(2H,m), 7. 76-7. 82(1 H,m),
8.08-8.35(2H,m),9.97(1 H,s),1 1 .1 (1 H,s).

Working Example No.548

5

[0949]

(1) A mixture of ethyl glycolate(9.64 g), 4-methoxybenzyl chloride (13.2 ml) ; and sodium hydride (3.89 g) in dimeth-
ylformamide (200 ml) was stirred overnight at 0 °C. The reaction mixture was diluted with ethyl acetate. The whole

10 was washed with water and brine and then dried over magnesium sulfate. After filtration, the filtrate was concen-

trated to leave a residue, which was purified by column chromatography on silica gel (Wakogel C-200, hexane-
ethyl acetate (20:1)) to afford the desired compound (16.0 g).

(2) A solution of acetonitrile (4.11 ml) in tetrahydrofuran (400 ml) was cooled to -78 °C. To the cooled solution, was
added n-butyllithium in hexane (1 .6 M, 46.3 ml) and the compound (1 6.0 g) obtained above in (1 ) in tetrahydrofuran

15 (150 ml) was added.

The reaction mixture was warmed up from -78°C to room temperature and stirred until the disappearence of the
starting material. To the reaction mixture, was added water and made acidic by the addition of 1 N hydrochloric
acid. The whole was extracted with ethyl acetate. To the organic layer, was added ethanol (200 ml) and hydrazine
monohydrate (20 ml). The mixture was refluxed overnight. The reaction mixture was concentrated to leave a res-

20 idue, which was purified by column chromatography on silica gel (Wakogel C-200, chloroform-methanol (98:2) to

afford the desired compound (13.9 g).

(3) A mixture of the compound (13.9 g) obtained above in (2), (Boc) 2 0 (15.1 ml), and sodium hydride (2.62 g) in
dimethylformamide (300 ml) was stirred at room temperature until the disappearence of the starting material. To
the reaction mixture was added saturated aqueous ammonium chloride and then extracted with ethyl acetate. The

25 organic layerwas washed with brine and dried over magnesium sulfate. After filtration, the filtrate was concentrated

to leave a residue, which was purified by column chromatography on silica gel (Wakogel C-200, hexane-ethyl
acetate (10:1-1 :1) to afford the desired compound (7.32 g).

(4) According to the procedure in working example No. 11 8(2), the desired compound(4.16 g) was obtained using
the compound(7.32 g) obtained above in (3).

30 (5) a mixture of the compound(4.1 6 g) obtained above in (4), and 1 0% Pd-carbon (3 g) in methanol-tetrahydrofuran

(1 : 1 )(1 40 ml) was stirred for 3 hours at 50 °C under an atmosphere of hydrogen. The reaction mixture was filtered
through a celite pad and the filtrate was concentrated to leave a residue, which was purified by column chroma-
tography on silica gel (Wakogel C-300, chloroform-methanol (98:2-80:20) to afford the compound A (602 mg),
which is protected by Boc and the titled compound (593 mg). 1 H-NMR(DMSO-d 6 )

35 0.98-1 .1 8(1 H,m),2.20-2.41 (2H,m),2.60-2.78(1 H,m),3.03-3.60(2H ,m),4.44(2H,d,J=5.5Hz),4.61 -4.79(1 H,m), 5.29

(1 H,t,J=5.5Hz),6.00(1 H,s),7.26(1 H,d,J=6.7Hz),7.42(1 H,dd J=6.7,7.9Hz),8.27(1 H,d,J=7.9Hz),9.41 (1 H,s),1 2.3
(1H,s).

mass:328(M+1) + .
40 Working Example No.549
[0950]

(1) According to the procedure in working example No. 84(1), the desired compound (295mg) was prepared from
45 the compound(51 Omg) in working example No.548.

(2) A mixture of the compound (121 mg) obtained above in (1) , 1 -methylpiperazine (414 uJ), and molecular sieve
3A (100 mg) in chloroform-methanol (1:1) (4ml) was stirred for 12 hours at room temperature. To the reaction
mixture, was added sodium hydrite (41 mg) and the mixture was stirred until the disapperance of the starting
material. The reaction mixture was filtered through a celite pad and the filtrate was concentrated to leave a residue,

50 which was purified by column chromatography on silica gel (Wakogel C-300, chloroform-methanol (20:1-4:1)) to

afford the recemic compound (139 mg).

(3) The recemic compound was subjected to optical resolution by HPLC (CHIRALPAK AD (DAICEL Chemical In-
dustries, Ltd.)) to afford the titled compound (A)(6mg) at Rt=8.3 min (CHIRALPAK AD (DAICEL Chemical Indus-
tries, Ltd., 0.46 § x 25 cm), ethanol, 0.5ml/min) and the compound (B)(19 mg) of the working example No. 550 at

55 Rt=11.1 min.

1 H-NMR(DMSO-d 6 )

0.98-1.13(1 H,m), 2.1 3(3H ; s), 2.22-2.47(1 OH, m), 2.51 -2.72(1 H,m), 3. 42(2H,s),3.23-3.60(2H,m), 4. 62-4. 78(1 H,m),
5.96(1H,s), 7.26(1 H,d,J=7.5Hz), 7.42(1 H,dd,J=7.5, 7 ,9Hz), 8.26(1 H,d,J=7.9Hz), 9.44(1H,s), 12.3(1H,s).

218

EP 1 199 306 A1

mass:410(M+1) + .
Working Example No.550

5 [0951] The compound of the working example No.550 was obtained as the optical isomer of working example No. 549.
mass:410(M+1)+.

Working Examples No.551-591

10 [0952] According to the procedure described in the working example No. 549(2), the compounds of the working ex-
amples from No. 551 to No. 591 were prepared.

Working Example No.551

15 [0953] 1 H-NMR(DMSO-d 6 )
0.82(6H,t,J=7.5Hz),0.98-

1 .14(1H,m),1 .36(4H,dq,J=7.2,7.5Hz),2.21-2.40(2H,m),2.48-2.65(2H,m),3.23-3.60(2H,m),3.67(2H,s),4.63-4.74(1H,
m), 6.02(1 H,s), 7.26(1 H,d,J=6.7Hz), 7.42(1 H,dd,J=6. 7,8.0Hz), 8. 26( 1 H,d, J=8.0Hz),9.41 (1 H,s), 12.2(1 H,s).
mass:397(M+1)+.

20

Working Example No.552
[0954] mass:383(M+1 )+.
25 Working Example No.553
[0955] mass:397(M+1 ) + .
Working Example No.554

30

[0956] mass:397(M+1)+.
Working Example No.555
35 [0957] mass:417(M+1)+
Working Example No.556
[0958] mass:41 7(M+1 )+.

40

Working Example No.557
[0959] mass:417(M+1)+.
^5 Working Example No.558
[0960] mass:445(M+1 ) + .
Working Example No.559

50

[0961] 1 H-NMR(DMSO-d 6 )

0.98-1.1 4(1 H,m),1.14(6H,d,J=6.9Hz), 2.24-2. 40(2H,m),2. 59-2. 70(1 H,m),2. 74(1 H,dq,J=6. 9, 6. 9Hz), 3. 22-3. 60(2H,m),
4.22(1 H,d,J=6.0Hz),4.64-4.73(1 H,m),5.94(1 H,t,J=6.0Hz), 6.08(1 H,s),6.40(1 H,d,J=7.0Hz),6.44(1 H,d,J=7.1 Hz), 6. 51
(1 H,s) ,6.98(1 H,dd,J=7. 0,7.1 Hz),7.26(1 H, d,J=7.0Hz), 7.42(1 H ,dd,J=7. 0,8.2Hz),8.25(1 H,d,J=8.2Hz),9.40(1 H,s),1 2.3
55 (1H,s).

219

EP 1 199 306 A1

Working Example No.560
[0962] mass:445(M+1 )+.
5 Working Example No.561
[0963] mass:443(M+1)+.
Working Example No.562

10

[0964] mass:431(M+1)+.
Working Example No.563
15 [0965] mass:439(M+1)+
Working Example No.564
[0966] mass:439(M+1 )+.

20

Working Example No.565
[0967] mass:443(M+1 )+.
25 Working Example No.566
[0968] mass:461 (M+1 ) + .
Working Example No.567

30

[0969] mass:399(M+1)+.
Working Example No.568
35 [0970] mass:399(M+1)+
Working Example No.569
[0971] mass:491(M+1)+.

40

Working Example No.570
[0972] mass:438(M+1 )+.
^5 Working Example No.571
[0973] mass:493(M+1 ) + .
Working Example No.572

50

[0974] mass:425(M+1)+.
Working Example No.573
55 [0975] mass:427(M+1)+.

220

EP 1 199 306 A1

Working Example No.574
[0976] mass:500(M+1 )+.
5 Working Example No.575
[0977] mass:436(M+1 )+.
Working Example No.576

10

[0978] mass:413(M+1)+.
Working Example No.577
15 [0979] mass:506(M+1)+
Working Example No.578
[0980] mass:503(M+1 )+.

20

Working Example No.579
[0981] mass:477(M+1)+.
25 Working Example No.580
[0982] mass:473(M+1 ) + .
Working Example No.581

30

[0983] mass:473(M+1)+.
Working Example No.582
35 [0984] mass:489(M+1)+
Working Example No.583
[0985] mass:489(M+1 )+.

40

Working Example No.584
[0986] mass:443(M+1 )+.
^5 Working Example No.585
[0987] mass:461 (M+1 ) + .
Working Example No.586

50

[0988] mass:522,524(M+1 )+.
Working Example No.587
55 [0989] mass:477(M+1)+.

221

EP 1 199 306 A1

Working Example No.588
[0990] mass:512(M+1)+.
5 Working Example No.589
[0991] mass:457(M+1)+.
Working Example No.590

10

[0992] mass:493(M+1)+.
Working Example No.591
15 [0993] mass:493(M+1)+

Working Examples No.592-595

[0994] According to the procedures described in the working example No. 549(2) and (3), the compounds of the
20 working examples from No. 592 to No. 595 were prepared.

Working Example No.592

[0995] mass:477(M+1 )+.

25

Working Example No.593
[0996] mass:477(M+1 )+.
30 Working Example No.594
[0997] mass : 477(M+1)+
Working Example No.595

35

[0998] mass:477(M+1)+.
Working Example No.596

40 [0999] According to the method in working example No. 290, the titled compound (15 mg) was obtained using the
compound(62 mg) in working example No. 662.
mass:397(M+1) + .

Working Example No.597

45

[1000] According to the procedure described in the working example No.596, the compound of the working example
No.597 was prepared.
mass:491 (M+1)+.

50 Working Example No.598

[1001] According to the method in working example No.596, the compound of the working example No.598 was
prepared from the compound in working example No. 649(2).
mass:501 (M+1)+.

55

222

EP 1 199 306 A1

Working Example No.599
[1002]

5 (l)According to the procedures in working example No. 548(2) and (3), the desired compound was prepared from

L-N-benzylproline ethyl ester.

(2) According to the procedure in working example No. 11 8(2), the desired compound was prepared(408 mg) from
the above compound(1)(623 mg).

(3) A solution of the compound (288 mg) obtained above in (2) in hydrochloric acid-methanol (5 ml) was stirred for
10 15 minutes at room temperature. The reaction mixture was concentrated and diluted with chloroform. The whole

was washed with saturated aqueous sodium bicarbonate and brine, and dried over magnesium sulfate. After fil-
tration, the filtrate was concentrated to leave a residue, which was purified by column chromatography on silica
gel (Wakogel C-200, chloroform-methanol (99:1)) to afford the desired compound (119 mg) as a mixture.

(4) The compound obtained above in (3) was subjected to optical resolution by HPLC to afford the titled compound
15 (38 mg) as fraction(A) at Rt=14.6 min (CHIRALCEL OD (DAICEL Chemical Industries, Ltd., 0.46 cp x 25 cm),

hexane-ethanol (80:20), 0.6ml/min) and the compound (39 mg) of the working example No. 600 as fraction(B) at

Rt=18.3 min.

mass:457(M+1) + .

20 Working Example No.600

[1003] Compound of working example No.600 was obtained as the diastereomer of the compound in working ex-
ample No.599.
1 H-NMR(DMSO-d 6 )

25 0.98-1.04(1 H,m), 1.64-1 .80(3H ! m),2.04-2.40(4H,m),2.59-2.90(2H,m),3.1 6(1 H,d,J=1 3Hz),3.42-3.60(3H,m), 3.76(1 H,
d,J=13Hz), 4.62-4. 68(1 Km), 6. 09(1 H,brs), 7. 20-7.36(6H, m), 7.42(1 H,dd,J=7. 9, 8.0Hz), 8.26(1 H,d,J=7.9Hz), 9. 43( 1H,s),
12. 4(11-1, s).
mass:457(M+1)+.

30 Working Example No.601

[1004] According to the procedures described in the working examples No.599 and No.600. D-N-benzylproline ethyl
ester was used to afford the titled compound (68 mg) as f raction(A) at Rt=1 4.0 min (CHIRALCEL OD (DAICEL Chemical
lndustries ; Ltd., 0.46 c)) x25 cm), hexane-ethanol (80:20), 0.6 ml/min) and the compound (64mg) of the working example
35 No. 602 as fraction(B) at Rt=1 6.8 min.
mass:457(M+1) + .

Working Example No.602

40 [1005] Compound of working example No.602 was obtained as the diastereomer of the compound in working ex-
ample No.601 .
mass:457(M+1) + .

Working Examples No.603-607

45

[1006] According to the procedures described in the working example No. 599(1 ) to (3), the compounds of the working
examples from No. 603 to No. 607 were prepared.

Working Example No.603

50

[1007] mass:388(M+1)+.
Working Example No.604
55 [1008] mass:424(M+1)+.

223

EP 1 199 306 A1

Working Example No.605
[1009] mass:389(M+1)+.
5 Working Example No.606
[1010] mass:424(M+1)+.
Working Example No.607

10

[1011] mass:388(M+1)+.
Working Example No.608

*s [1012] A mixture of the compound (61 0 mg) of the working example No. 599, 1 0% Pd-carbon catalyst (300 mg), and
ammonium formate (800 mg) in ethanol (15 ml) was refluxed for 4 hours. The reaction mixture was cooled to room
temperature and then filtered through a celite pad. The filtrate was concentrated to leave a residue, which was purified
by column chromatography on silica gel (Silica gel 60N(spherial neutral)(Kanto Kagaku Co. Ltd., chloroform-methanol
(98:2-5:1)) to afford the titled compound (290 mg).

20 mass : 367 (M+1) + .

Working Example No.609
[1013] mass:367(M+1)+.

25

Working Example No.61 0
[1014] mass:367(M+1)+.
30 Working Example No.61 1

[1015] mass : 367 (M+1)+.
Working Example No.61 2

35

[1016] According to the procedures described in the working example No. 599(1) to (3), the compound of the working

example No.61 2 was prepared.

mass:375(M+1)+.

40 Working Example No.61 3

[1017]

(1) According to the procedure in working example No. 11 8(1), the desired compound(1 .35 g) was prepared from
45 2-chloro-3-cyanopyridine(1 .87 g).

(2) According to the procedure in working example No. 548(3), the N-protected compound(618 mg) was prepared
from the above compound(1 )(81 8 mg).

(3) According to the procedure in working example No.118(2), the titled compound was obtained(45 mg) using the
compound (294 mg) described above in (2).

50 1 H-NMR(DMSO-d 6 )

1 .04-1 .20(1 H,m),2.30-2.41 (2H,m),2.62-2.71 (1 H,m),3.28-3. 35(1 H,m),3. 48-3.59(1 H,m),4. 74-4.82(1 H,m),

7,1 2-7.20(1 H, m), 7. 33(1 H ,d,J=7.6Hz), 7.48(1 H,ddJ=7.6,7.9Hz),8.32( 1 H,d,J=7.9Hz), 8.51 -8.54(2H,m), 9.80(1 H,

s), 10.2(1 H,s).

mass:349(M+1)+.

55

Working Examples No.61 4-61 5

[1018] According to the procedures described in the working example No. 599(1 ) to (3), the compounds of the working

224

EP 1 199 306 A1

examples from No. 61 4 to No. 61 5 were prepared.
Working Example No.614
5 [1019] mass:468(M+1)+.
Working Example No.615
[1020] mass:380(M+1)+.

10

Working Examples No.616-619

[1021] According to the procedures described in the working example No. 599(1) to (3), compounds of working ex-
amples from No. 61 6 to No. 61 9 were prepared from the compounds in working examples No. 306(3) and compounds
*s synthesized according to the procedures in working examples No.306(2)-B to (3).

Working Example No.61 6

[1022] mass:366(M+1)+.

20

Working Example No.61 7
[1023] mass:366(M+1)+.
25 Working Example No.61 8
[1024] mass:473(M+1) + .
Working Example No.61 9

30

[1025] mass:473(M+1)+.

Working Examples No.620-621

35 [1026] According to the procedures described in the working example No. 548(5), the compounds of the working
examples from No. 620 to No. 621 were prepared using compounds in working examples No.61 8 and No.61 9.

Working Example No.620

40 [1027] mass:383(M+1)+.

Working Example No.621

[1028] mass:383(M+1)+.

45

Working Examples No.622-625

[1029] The compounds of the working example No. 306(3) and the compounds synthesized in the working examples
No.306(2)-B to No. 306(3), were used to afford the corresponding diastereomers, which were subjected to resolution
50 by HPLC (CHIRALPAK AD (DAICEL Chemical Industries, Ltd. ,2 <|> X 25 cm)) following the the procedures described
in the working example No. 599(1) to (3) to afford the compounds of the working examples No. 622 to 625.

Working Example No.622

55 [1030] mass:471(M+1)+.

225

EP 1 199 306 A1

Working Example No.623
[1031] mass:471(M+1)+.
5 Working Example No.624
[1032] mass:471(M+1)+.
Working Example No.625

10

[1033] mass:471(M+1)+.
Working Example No.626

*s [1034] According to the procedures described in the working example No. 599(1 ) to (3), the compounds of the working
example No.626 was prepared.
mass:471 (M+1)+.

Working Example No.627

20

[1035] According to the procedure described in the working example No. 622, the compound of the working example

No.627 was prepared.

mass:424(M+1)+.

25 Working Examples No.628-629

[1036] According to the procedure described in the working example No. 622, the compounds of the working examples
No. 628 and No. 629 were prepared.

30 Working Example No.628

[1037] mass:424(M+1)+.

Working Example No.629

35

[1038] mass:424(M+1)+.
Working Example No.630
40 [1039]

(1) According to the procedure in working example No. 610, the desired compound was prepared from the com-
pound in working example No. 599(3).

(2) A mixture of the compound (85 mg) obtained above in (1) and N-(diethylcarbamoyl)-N-methoxyformamide (81
45 uj) in chloroform (2 ml) was stirred for 2 hours at 60 °C. The reaction mixture was cooled to room temperature and

diluted with chloroform. The whole was washed with water and brine and dried over magnesium sulfate. After
filtration, the filtrate was concentrated to leave a residue, which was purified by TLC (Merck Art5744, chloroform-
methanol(1 0:1)) to afford a mixture of diastereomers, which was subjected to resolution following the procedure
described in the working example No. 549(3) to afford the titled compound (4 mg) and the compound (3 mg) of the
50 working example No. 631 .

mass:395(M+1) + .

Working Example No.631

55 [1040] mass:395(M+1)+.

226

EP 1 199 306 A1

Working Example No.632
[1041]

5 (1 )Diastereomer mixture(70 mg) was prepared from the compound in working example No. 630(1 71 mg) according

to the procedure in working example No. 295.

(2)The above compound was resolved in the same way as that in the working example No. 549(3) to afford the

compounds of working examples No. 632(13 mg) and No. 633(26 mg).

mass:381(M+1)+.

10

Working Example No.633

[1042] The compound of working example No.633 was obtained as the diastereomer of the compound of working
example No.632.
15 mass:381(M+1)+.

Working Example No.634

[1043] The compound in working example No. 636(42 mg) and 1 -butylamine(120[o.l_) were reacted according to the
20 procedure in working example No. 549(2). The mixture was treated with 1 0% HCI-MeOH and dried to afford the titled
compound as a hydrochloride(22 mg).
mass:397(M+1) + .

Working Example No.635

25

[1044] According to the procedure described in the working example No.634, the compound of the working examples
No.635 was prepared.

Working Example No.636

30

[1045] Afterthe compound of working example No.639(2)(1 .20 g) was reacted according to the procedure described
in working example No. 84(1), the compound obtained above was reacted according to the procedure described in
working example No. 599(3) to afford the titled compound(591 mg).
mass:340(M+1)+.

35

Working Example No.637

[1046] According to the procedure described in the working example No. 599(3), the titled compound(708 mg) was
obtained from the compound in working example No. 639(1).
40 mass:432(M+1)+.

Working Example No.638

[1047] According to the procedure described in the working example No.634, the compound of the working examples
45 No.638 was prepared.

Working Example No.639

[1 048]

50

(1) According to the procedures in working example No. 599(1) and (2), the desired compound was prepared from
ethyl 2-benzyloxypropionate.

(2) The compound obtained above in (1)(4.30 g) was reacted in the same conditions as that described in working
example No. 548(5). 10% HCI-MeOH was added to the mixture to remove Boc group. Ethyl acetate was added

55 and the crystal precipitated was filtrated and then dried to afford the titled compound(2.21 g).

mass:342(M+1)+.

227

EP 1 199 306 A1

Working Examples No.640-646

[1049] According to the procedure described in the working example No. 634, the compounds of the working examples
from No. 640 to No. 646 were prepared.

5

Working Example No.640
[1050] mass:369(M+1)+.
10 Working Example No.641
[1051] mass:383(M+1)+
Working Example No.642

15

[1052] mass : 445 (M+1)+
Working Example No.643
20 [1053] mass:409(M+1)+.
Working Example No.644
[1054] mass:381(M+1)+.

25

Working Example No.645
[1055] mass:383(M+1)+.
30 Working Example No.646
[1056] mass:409(M+1)+.
Working Example No.647

35

[1057]

(l)According to the procedure in working example No. 548(2), the desired compound was prepared from L-N-
benzylproline ethyl ester.

40 (2)A mixture of the compound (1 .34 g) obtained above in (1 ), sodium hydride(243 mg), and methyliodine (0.38 ml)

in dimethylformamide (20 ml) was stirred at room temperature until the diappearence of the starting material. To
the reaction mixture, was added saturated aqueous ammonium chloride and the whole was extracted with ethyl
acetate. The organic layer was washed with water and then dried over magnesium sulfate. After filtration, the
filtrate was concentrated to leave a residue, which was purified by column chromatography on silica gel (Wakogel

45 C-300, chloroform-methanol (98:2) to afford the desired compound (350 mg).

(3) The compound obtained above in (2)(340 mg) was treated according to the procedure in working example No.
118(2) to afford the desired compound(252 mg).

(4) According to the procedure in working example No. 610, the diastereomer mixture(86 mg) was prepared from
the compound obtained above in (3)(252 mg). The mixture was resolved in the same procedure as that in working

50 example No. 549 to afford the titled compound(20 mg) and its diestereomer(1 7 mg) which is the compound in

working example No. 648.
mass:381(M+1)+.

Working Example No.648

55

[1058] The compound of working example No.648 was obtained together with the compound in working example
No.647.

mass:381(M+1)+.

228

EP 1 199 306 A1

Working Example No.649
[1059]

5 (l)According to the procedures in working example No. 548(1) and (2), the desired compound was prepared from

ethyl glycolate and benzylbromide.

(2) The mixture of the compound obtained above in (1)(1 .31 mg), sodium hydride(271 mg), and methyliodine(421(a,
L) in dimethyl formamide(30 ml_) was stirred at 0 °C for 60 minutes and then treated by the general method. The
residue was purified by column chromatography on silica gel(Wakogel C-200, chloroform-methanol(99:1 to 98:2)

10 to afford the desired compound(593 mg).

(3) According to the procedure in working example No.1 1 8(2), the desired compound(535 mg) was prepared using
the compound (593 mg) obtained above in (2).

(4) According to the procedures in working examples No. 548(5) and followed by 84(1), the desired compound(1 76
mg) was prepared using the compound obtained above in (3).

15 (5) Using the compound obtained above in (4)(30 mg) and 2-aminoindan(31 mg). the titled compound(31 mg) and

the compounds in working examples No. 650(11 mg) and No.651(12 mg) were obtained according to the procedure
in working examples No. 549(2).
1 H-NMR(DMSO-d 6 )

0.93-1 .1 0(1 H,m),2.24-2.38(2H,m),2.52-2.63(1 H,m), 2.67(1 H,d,J=6.6Hz), 2. 72(1 H,d,J=6.6Hz),3.02(1 H,d,J=7.0Hz),3.
20 08(1H,d,J=7.OHz) ; 3.28-3.58(3H,m),3.72(3H,s), 3.74(2H,s),4. 71 -4.80(1 Km), 6. 08(1 H,s),7. 06-7. 18(4H,m), 7.26(1 H,

d,J=7.4Hz), 7.43(1 H,dd,J=7.4,7.9Hz), 8.26(1 H,d,J=7.9H z),9.43(1 H,s).
mass : 457 (M+1) + .

Working Example No.650

25

[1060] The compound of working example No.650 was obtained as a by-product of thecompound of working example
No.649.

mass:386(M+1)+.

30 Working Example No.651

[1061] The compound of working example No.651 was obtained as a by-product of thecompound of working example
No.649.

mass:342(M+1)+.

35

Working Examples No.652-656

[1062] According to the procedure described in the working example No.649, the compounds of the working examples
from No. 652 to No. 656 were prepared.

40

Working Example No.652
[1063] mass:487(M+1)+.
45 Working Example No.653
[1064] mass:475(M+1) + .
Working Example No.654

50

[1065] mass:535,537(M+1 )+.
Working Example No.655
55 [1066] mass:491(M+1)+.

229

EP 1 199 306 A1

Working Example No.656

[1067] mass:491(M+1)+.

5 Working Examples No.657-687

[1068] According to the procedure described in the working example No. 549(2), the compounds of the working ex-
amples from No. 657 to No. 687 were prepared.

10 Working Example No.657

[1069] mass:383(M+1)+

Working Example No.658

15

[1070] mass:409(M+1)+.
Working Example No.659
20 [1071] mass:417(M+1)+.
Working Example No.660
[1072] mass:369(M+1)+.

25

Working Example No.661
[1073] mass:369(M+1)+.
30 Working Example No.662

[1074] 1 H-NMR(DMSO-d 6 )

0.95-1 .12(1 H,m),1 .36(9H,s), 2. 22-2. 38(2H,m), 2. 62-2. 75(1 H, m),3. 23-3.37(1 H,m), 3. 42-3. 60(1 H,m),4. 1 0(2H ,m), 4.79
(1H,dd,J=5.9,10Hz),6.47(1H,s),7.29(1H,d,J=7.3Hz),7.45(1 H,t,J=7.3Hz), 8.22(1 H,d,J=7.3Hz), 9.09(3H,br) ; 9.91(1H,
35 S ).

mass:383(M+1)+.

Working Example No.663

40 [1075] mass:355(M+1)+.

Working Example No.664

[1076] mass:395(M+1)+.

45

Working Example No.665
[1077] mass: 381 (M+1)+.
50 Working Example No.666
[1078] mass:341 (M+1)+.
Working Example No.667

55

[1079] mass:324(M+1) + .

230

EP 1 199 306 A1

Working Example No.668
[1 080] 1 H-N M R (DM SO-d 6 )

0.90-1 .20(1 H,m) ,1 .20-2. 00(8H ; m), 2.20-2. 70(4H,m),3.00-3. 40(1 H,m),3. 40-3. 60(1 H,m),3.74(2H,m),4.69(1 H,m), 7.25
5 (1H,d,J=7.9Hz),7.41(1H,t,J=7.9Hz),8.21(1H,d,J=7.9Hz),9. 44(1 H,br), 12.2(1 H,br).
mass:395(M+1)+.

Working Example No.669

10 [1081] mass:383(M+1)+

Working Example No.670

[1082] mass:397(M+1)+.

15

Working Example No.671
[1 083] 1 H-N MR(DMSO-d 6 )

0. 70-0. 95(6H,m),0. 95-1 .15(1 Km), 1 .15-1 .50(8H,m),2.1 0-2. 70(4H,m),3.1 0-3.40(1 H,m),3. 40-3. 60(1 H,m),3.66(2H,s),
20 4.70(1H,dd,J=6.0,11Hz),6.01(1H,br),7.27(1Kd,J=7.9Hz)7.43^ 1 H,t,J=7.9Hz), 8. 27(1 H,d,J=7.9Hz), 9.40(1 H,s),1 2.1
(1H,br).

mass:425(M+1) + .
Working Example No.672

25

[1084] mass:425(M+1) + .
Working Example No.673
30 [1085] mass:439(M+1)+.
Working Example No.674
[1086] mass:411(M+1)+.

35

Working Example No.675
[1087] mass:397(M+1) + .
40 Working Example No.676
[1088] mass:411(M+1) + .
Working Example No.677

45

[1089] mass:445(M+1)+.
Working Example No.678
50 [1090] mass:445(M+1) + .
Working Example No.679
[1091] mass:445(M+1)+.

55

Working Example No.680
[1092] mass:481(M+1)+.

231

EP 1 199 306 A1

Working Example No.681
[1093] mass:481(M+1)+.
5 Working Example No.682
[1094] mass:437(M+1)+.
Working Example No.683

10

[1095] mass:468(M+1)+.
Working Example No.684
15 [1096] mass:489(M+1)+
Working Example No.685
[1097] mass:484(M+1)+.

20

Working Example No.686
[1098] mass:459(M+1)+.
25 Working Example No.687
[1099] mass:399(M+1) + .
Working Example No.688

30

[1100]

(1) A mixture of 2-aminoindan hydrochloride (1.93 g), bromine (5.0 ml) and acetic acid (30 ml) was stirred for 3
days at 50 °C. The reaction mixture was concentrated to leave a residue, which was dissolved in chloroform (50

35 ml). (Boc) 2 0 (4 ml) and triethylamine (15 ml) were added and the reaction mixture was stirred until the disap-

pearence of the starting material. The mixture was washed with 1 N hydrochloric acid. The organic layer was con-
centrated to leave a residue, which was purified by column chromatography on silica gel (Wakogel C-200) to afford
the desired compound (1 .38 g).

(2) According to the procedure in working example No. 599(3), the titled compound(553 mg) was prepared using
40 the compound (1 .38 g) obtained above in (1).

(3) A mixture of the compound(14 g) obtained above in (2), ethyl bromoacetate (5.85 ml), and triethylamine (14.7
ml) in toluene (1 00 ml) was stirred at room temperature overnight. The mixture was diluted with ether-ethyl acetate.
The whole was washed with brine and dried over magnesium sulfate. After filtration, the filtrate was concentrated
to leave a residue, which was dissolved in chloroform (150 ml) and (Boc) 2 0 (12.6 ml) was added again. The

45 reaction mixture was stirred at room temperature until the disappearence of the starting material. The mixture was

concentrated to leave a residue, which was purified by column chromatography on silica gel (Wakogel C-200,
hexane-ethyl acetate) to afford the desired compound (11 .68 g).

(4) According to the procedure in working example No. 548(2), the compound (1 0.13 g) obtained above in (3) was
used to afford the desired compound (1 .95 g).

50 (5)Urea was prepared according to the procedure in working example No. 11 8(2) using the compound obtained

above in (4) and amine synthesized from 3-hydroxy-2-butanone according to the procedures in working example
No. 533(1) to (3).

(6)The compound obtained above in (5) was treated by 4N HCI-dioxane to remove the Boc-protected group and
the titled compound was obtained.
55 mass:551 ,553(M+1 )+.

232

EP 1 199 306 A1

Working Examples No.689-690

[1101] According to the procedure described in the working example No. 688, the compounds of the working examples
No. 689 and No. 690 were prepared.

5

Working Example No.689
[1 1 02] 1 H-N M R(DM SO-d 6 )

0. 78-1. 20(7H,m), 2. 24-2. 78(4H ; m), 2. 89-3. 1 0(2H,m),3.40-3. 59(1 H,m),3.72(2H,s), 4.1 0-4.22(1 H,m),4.78(1 H,s), 6.10
10 (1 H,brs), 7.27(1 H,d,J=6.5Hz), 7.29(1 H,d,J=7.7Hz),7.35(1 H, d, J=6.5Hz), 7. 40(1 H,s),7.48(1 H,dd,J=7. 7,8. 5Hz), 8.32(1 H,
d,J=8 .5Hz),9.55(1 H,s),12.1 (1 H,brs).
mass:565 ! 567(M+1)+.

Working Example No.690

15

[1103] mass:551,553(M+1)+.

Working Examples No.691-692

20 [1104] According to the procedure described in the working example No. 693, the compounds of the working examples
No. 691 and No. 692 were prepared.

Working Example No.691

25 [1105] mass:548(M+1) + .

Working Example No.692

[1106] mass:474(M+1)+.

30

Working Example No.693
[1107]

35 (l)According to the procedure in working example No. 409(1), the compound (54 mg) of the working example No.

120, trans-1 ,4-diaminocyclohexane protected by mono Boc group(56 mg), which was prepared from the reaction
of trans-1 ,4-diaminocyclohexane and (Boc) 2 0 in chloroform following the ordinary method, to afford the desired
compound (61 mg).

(2)According to the procedure in working example No. 548(2), the titled compound(37 mg) was obtained from the
40 compound (61 mg) described above in (1).

1 H-NMR(DMSO-d 6 )

0.98-1.20(1 H,m), 1.48-1 .53(4H,m),1 .88-2. 09(4H, m) ,2.26-2. 43(2H ,m), 2. 63-2. 71 (1 H,m), 2. 90-3. 08(1 H,m),
3.23-3. 83(3H,m), 4. 74-4. 85(1 H,m),6.71 (1 H,s), 7.26(1 H ,d,J=7.4Hz), 7.44(1 H,dd,J=7.4,7.9Hz), 7.54(1 H,dd,
J=7. 7,8.3Hz), 7. 80(1 H,d,J=8.3Hz), 7. 88(1 H,d,J=7.7H z), 8. 02-8. 1 3(2H ,br),8.23(1 H,s),8.26(1 H,d,J=6.6Hz), 8.48
45 (1H,d,J=7.9Hz),9. 20-9. 40(1 H,br), 9. 84(1 H,s).

mass:514(M+1)+.

Working Examples No.694-700

50 [1108] According to the procedure described in the working example No.693, the compounds of the working examples
from No. 694 to No. 700 were prepared.

Working Example No.694

55 [1109] mass:490(M+1)+.

233

EP 1 199 306 A1

Working Example No.695
[1110] mass:514(M+1)+.
5 Working Example No.696
[1111] mass:514(M+1)+.
Working Example No.697

10

[1112] mass:560(M+1)+.
Working Example No.698
15 [1113] mass:527(M+1)+
Working Example No.699
[1114] mass:536(M+1)+.

20

Working Example No.700

[1115] mass:528(M+1)+.

25 Working Example No.701

[1116] According to the method described in working example No. 11 8(4), the titled compound (69 mg) was obtained

from the compound in working example No. 703(1 00 mg).

mass:298(M+1)+.

30

Working Example No.702
[1117]

35 (l)According to the procedure in working example No. 703, the desired compound was prepared from 3-amino-

4-ethoxycarbonyl pyrazole.

(2)According to the procedure in working example No. 1 1 8(4). thetitled compound was obtained from the compound

(300 mg) obtained above in (1).

mass:370(M+1)+.

40

Working Example No.703
[1118]

^5 (1) A mixture of 3-aminopyrazole (3.00 g), benzylbromide (5.60 g), and sodium hydride (1 .72 g) in dimethylforma-

mide (30 ml) was stirred for 3 hours at room temperature. To the reaction mixture, was added saturated aqueous
ammonium chloride and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. After
filtration, the filtrate was concentrated to leave a residue, which was purified by column chromatography on silica
gel (Wakogel C-200, hexane-ethyl acetate(3:1 -1 :1)) to afford the desired compound (2.87 g).

50 (2) According to the procedure in the working example No. 118(2), the compound (2.89 g) obtained above in (1)

was used to afford the titled compound (989 mg).
mass:388(M+1) + .

Working Example No.704

55

[1119]

(1 )A solution of the compound (300 mg) of the working example No. 702(1 ) in tetrahydrofuran (20 ml) was cooled

234

EP 1 199 306 A1

to 0 °C and lithium aluminum hydride (30 mg) was added. The mixture was stirred for 30 minutes and 1 N hydro-
chloric acid was added. The whole was extracted with ethyl acetate.

The organic layer was washed with brine and dried over magnesium sulfate. After filtration, the filtrate was con-
centrated to leave a residue, which was purified by column chromatography on silica gel (Wakogel C-200, hexane-
5 ethyl acetate(1 : 1 -1 :2)) to afford the titled compound (248 mg).

mass:418(M+1)+.

Working Example No.705

10 [1120] According to the procedure described in working example No. 11 8(2), the titled compound (1 96 mg) was ob-
tained from 3-amino-1 -methyl pyrazole(100 mg).
mass:312(M+1)+.

Working Example No.706

15

[1121]

(1) A solution of the compound (280 mg) of the reference example No. 3 in chloroform (5ml) was bubbled by chlorine
gas to afford a crude product, which was collected by filtration. The crude product was dissolved in a mixture of

20 aqueous sodium hydroxide and chloroform. The organic layer was separated and then concentrated to leave a

residue, which was purified by TLC (Merck Art5744, chloroform-methanol(1 0:1)) to afford monochloride (A) (84
mg) and dichloride (B)(66 mg).

(2) According to the procedure in working example No.1 , the titled compound was obtained as a white cystal from
the compound obtained above in (1)-A(42 mg).

25 mass:343(M+1)+.

Working Example No.707
[1122]

30

(1) A solution of the compound (2.02 g) of the reference example No. 3 in chloroform was cooled to -20 °C and
bromine (1.16 ml) was added. The mixture was stirred for 10 minutes and warmed up to room temperature. The
precipitation was collected by filtration, which was dissolve in a mixture of aqueous sodium hydroxide and chloro-
form. The organic layer was separated and then concentrated to leave a residue, which was purified by TLC

35 (Wakogel C-200, chloroform-methanol (99:1)) to afford monobromide (A) (1 .30 g) and dibromide (B)(1 .14 g).

(2) According to the procedure in working example No. 1 , the titled compound(1 .24 g) was obtained from the compound
obtained above in (1)-A(1.03 g).

1 H-NMR(DMSO-d 6 )

0.98-1.1 4(1 H,m),2.22-2.40(2H,m),2.43-2. 60(1 H,m),3.27-3. 40(1 H,m),3.49-3. 60(1 H,m), 4.73-4.80(1 H,m), 7.06(1 H,dd,
40 J=7.2,1 2Hz), 7.26(1 H, d,J=8.7Hz), 7.59(1 H,d,J=8.4Hz), 7.79(1 H,ddd,J=2.1 ,8. 7,12Hz), 8.30(1 H,dd,J=2.1 ,7.2Hz), 8.26

( 1 H,d,J=8.4Hz),1 0.0(1 H,s),11 .3(1 H,s).
mass:387,389(M+1) + .

Working Example No.708

45

[1123] According to the method described in the working example NO.1 , the titled compound was obtained from the

compound obtained in working example No. 707(1 )-B.

mass:467 : 469(M+1) + .

50 Working Example No.709

[1124] According to the method described in the working example No.1 , the titled compound was obtained from the

compound (37 mg) obtained in working example No. 706(1 )-B.

mass:378(M+1)+.

235

EP 1 199 306 A1

Working Example No.71 0
[1125]

5 (1) According to the procedure in working example No. 56, a light yellow solid(121 mg) as a mixture of two com-

pounds was prepared from 4-nitro-1 ,2-benzoisothiazole -3-one-1 ,1 -dioxide (1 00 mg) and 2-propanol(67
(2)The mixture obtained above in (1)(30 mg) was reacted in the same conditions as that in reference example No.
3. The raw product was purified with TLC(Merck Art5744, chloroform -methanol, 80:1) to yield N-alkylcompound
(A) (6mg) and O-alkylcompound(B) (20 mg).

10 (3)According to the procedure in working example No.1 , the titled compound was obtained from the compound (6

mg) obtained above in (2)-A.
1 H-NMR(CDCI 3 )

1 .65(6H,d,J=7.8Hz),4.55(1H,dq,J=7.8,7.8Hz),6.95(1H,d,J=7.8H z), 7.04(1 H,t,J=6.3Hz), 7.47(1 H ,d,J=7.5Hz),7.61
(1 H,br), 7. 66-7.78(1 H,m), 8.47(1 H,d,J=5.7Hz) ; 9.00(1 H,d,J=8.4Hz),1 3.1 (1 H,br ).
15 mass:361(M+1)+.

Working Example No.71 1

[1126] According to the method described in the working example No.1 , the titled compound was obtained as a light
20 yellow solid (93 mg) from the compound (75 mg) obtained above in working example No.71 0(2)-B.
1 H-NMR(CDCI 3 )

1 .45(6H,d,J=6Hz),5.49(1H,dq,J=6,6Hz),6.85(1H,d,J=8.1Hz),7.0 3-7.07(1 H ,m), 7.59-7. 75(3H,m), 8.27-8. 30(1 H,m),

8.36(1H,d,J=9.3Hz),11.8(1H,br).

mass:361 (M+1)+.

25

Working Examples No.71 2-71 3

[1127] Compounds of working examples No.71 2-71 3 were prepared according to the procedures described in work-
ing examples No.71 0 and No. 711.

30

Working Example No.71 2
[1128] mass:387(M+1)+.
35 Working Example No.71 3
[1129] mass:387(M+1) + .
Working Example No.71 4

40

[1130] The compound (55 mg) of the working example No. 711 was dissolved in tetrahydrofuran (4 ml) and sodium
borohydride (17 mg) was added. The mixture was stirred for 30 minutes at room temperature. To the reaction mixture
was added aqueous sodium bicarbonate and extracted with chloroform. The organic layer was washed with saturated
brine and then dried over magnesium sulfate. Ater filtration, the filtrate was concentrated to leave a residue, which was
45 purified to TLC (Merck Art5744, chloroform-methanol(80:1)) to afford the titled compound (5 mg) as a white solid.
1 H-NMR(DMSO-d 6 )

4.41 (2H,br),7.04(1 H,t,J=6Hz),7.40(1 H,d,J=7.2Hz), 7.47(1 H,d,J =8.1 Hz), 7.56(1 H,t,J=8.1 Hz), 7. 75-7. 87(2H,m), 8.25-8.33

(2H,m), 9.84(1H,s),10.9(1H,br).

mass:305(M-i-1) + .

50

Working Example No.71 5

[1131] According to the procedure described working example No. 56, the titled compound was obtained as a white
solid(3 mg) from the compound obtained above in working example No.71 4(5 mg) and 2-propanol(7jxl_).
55 1 H-NMR(CDCI 3 )

1 .46(3H,t,J=7.2Hz),4.47(2H,q,J=7.2Hz),4.94(2H,s),6.83(1 H,d, J=8.1 Hz), 7.04(1 H,t,J=8.4Hz) ; 7.54(1 H ; d,J=6.9Hz),
7.61(1H,t,J= 8.1Hz), 7.73(1 H,tJ=8.7Hz), 7.97(1H,s), 8.33(1 H,dJ=3.3Hz), 8.4 6(1 H ,d,J=7.8Hz), 12.5(1H,s).
mass: 377 (M+1)+.

236

EP 1 199 306 A1

Reference Examples of the Invention

Reference Example No.1

5 [1132] A mixture of 9-fluorenone-4-carboxylic acid (10.0 g, 44.6 mmol), and thionyl chloride (50 ml) in dimethylfor-
mamide (1 ml) was refluxed for 1 hour. The reaction mixture was concentrated to afford an acid chloride of the titled
compound as a yellow solid, which was used for the next reaction without further purification.

Sodium azide (4.06 g, 62.5 mmol) was dissolved in water (50 ml) and cooled in an ice-bath. To the solution was added
the suspension of the acid chloride obtained above in tetrahydrofuran (200 ml) in one portion. The reaction mixture

10 was stirred for 1 hour at the same temperature and then extracted with tetrahydrof uran-ethyl acetate (1 0: 1 ). The organic
layer was separated and washed with brine and dried over magnesium sulfate. After filtration, the filtrate was concen-
trated to leave a crystal precipitated, from which the titled compound (1 0.3 g) was obtained by filtration.
1 H-NMR(CDCI 3 )5:7.29-7.43(2H,m), 7. 56(1 H,dt,J=7.7Hz, 1.3Hz), 7.75(1 H,dJ=7.5Hz),7.90(1 H,dd,J=7.3Hz,1 .3Hz),8.02
(1 H,dd,J=7 .9Hz,1 .2Hz), 8.43(1 H ; d,J=7.9Hz).

15 mass:250(M+1)+.

Reference Example No.2
[1133]

20

(1) 2-chloro-3-nitrobenzoic acid (2 g, 10.0 mmol) was mixed with thionyl chloride (30 ml) at room temperature.
4-Dimethylaminopyridine (122 mg, 1.00 mmol) was added. The reaction mixture was refluxed for 12 hours and
then concentrated to afford a crude acid chloride. To a solution of pyrrole (3.5 ml, 50.0 mmol) and triethylamine
(7.0 ml, 50.0 mmol) in methylenechloride (80 mL), was added above-mentioned acid chloride at room temperature.

25 The reaction mixture was stirred for 6 hours at the same temperature and then diluted with ethyl acetate. The

whole was washed with brine and dried over magnesium sulfate. After filtration, the filtrate was concentrated to
leave a residue, which was purified by column chromatography on silica gel (hexane-ethyl acetate, 1:0-7:3) to
afford a yellow oil (2.43 g).

(2) To a solution of the yellow oil (2.40 g, 9.60 mmol) obtained above in (1) in dimethylacetoamide (180 mL) was
30 added potassium acetate (1 .80 g, 1 9.2 mmol). The air in the reactor was replaced by nitrogen. To the mixture, was

added tetrakistriphenylphosphine palladium (1 .10 g, 0.960 mmol) at room temperature. The reaction mixture was
stirred overnight at 130°C and then diluted with ethyl acetate-ether (1 :2). The whole was washed with water and
brine in turn and dried over magnesium sulfate. After filtration, the filtrate was concentrated to leave a residue,
which was purified by column chromatography on silica gel (hexane-chloroform, 1 :0-1 :1) to afford the titled com-
35 pound (2.24 g) as a brown solid.

1 H-NMR(CDCI 3 )5:6.34(1H,t,J=3.2Hz), 7.1 0(1 H,dd,J=3.3Hz,0.85Hz),7.21 (1 H,m), 7.35(1 H,dd J J=8.3Hz,7.3Hz),
7.94(1 H,dd,J=7.3Hz,1 ,0Hz),8.28(1 H ,dd,J=8.5Hz,1 .0Hz).

Reference Example No.3

40

[1134] To a solution of the compound (2.24 g) of the reference example No.2 in methanol-tetrahydrofuran (1 :1) (80
ml) was added 10% palladium-carbon catalyst (0.200 g) at room temperature. The reaction mixture was stirred for 12
hours at room temperature under an atmosphere of hydrogen. The insoluble material was removed by filtration with
celite and the filtrate was concentrated to leave a residue, which was purified by column chromatography on silica gel
^5 (chloroform-methanol, 1 :0-98:2-95:5) to afford the titled compound (1 .03 g) as a brown solid.

1 H-NMR(DMSO-d 6 )5:0. 80-0.93(1 H,m),2.1 0-2. 30(2H,m), 2.43-2. 51 (1 H,m),3.1 8-3.24(1 H,m), 3. 38-3.47(1 H,m), 4.50(1 H,
dd,J=1 0Hz,5.5Hz),5.34(2H,s),6.72(1 H,d,J=7.9Hz),6.76 (1 H ; d,J=7.4Hz),7. 1 1 (1 H,t,J=7.6Hz).

Reference Example No.4

50

[1135] To a cooled ethanol (90 mL) was added sodium (500 mg, 22 mmol) under an atmosphere of nitrogen. The
reaction mixture was stirred for 50 minutes at room temperature and then cooled in an ice-bath. To the cooled reaction
mixture was added a solution of 4-[2-[[(1 ,1 -dimethylethyl)diphenylsilyl] oxy]ethyl]- 2-pyridinecarbonitrile (45 g, 120
mmol) in ethanol (1 50 mL) over a period of 1 5 minutes. The reaction mixture was warmed up to room temperature and
55 stirred for 4 hours. Under an ice-bath, the reaction mixture was made acidic by adding 1 N hydrochloric acid (1 20 ml,
120 mmol) and further to this, water (50 ml) was added at the same temperature. The whole was extracted with ethyl
acetate. The organic layer was washed with water, 1 N sodium hydroxide and brine in turn, and dried over magnesium
sulfate. After filtration, the filtrate was concentrated to leave a brown oil, which was purified by column chromatography

237

EP 1 199 306 A1

on silica gel (hexane-ethyl acetate, 2:1 -1:1) to afford the titled compound (42 g) as a yellow oil.
1 H-NMR(CDCI 3 )5:1.00(9H,s),1.45(3H,t ! J=7.0Hz),

2.89(2H,t,J=6.3Hz), 3.90(2H,t, J=6.3Hz), 4.49(2H,q,J=7.0Hz), 7. 28(1 H,d,J=4.9Hz), 7.32-7.45(6H,m), 7.55(4H, dd),
7.99(1H,s), 8.62(1 H ,d.J=5.6Hz).

5

Reference Example No.5
[1136]

10 (1 ) To a solution of the compound (13 g. 32 mmol) of the reference example No. 4 in methanol (200 mL) was added

hydrazine monohydrate (7.8 mL, 160 mmol) at room temperature. The reaction mixture was stirred for 19 hours
in the same temperature and diluted with chloroform, and washed with brine. The organic layer was dried over
magnesium sulfate. After filtration, the filtrate was concentrated to afford a yellow oil (14 g), which was used for
the next reaction without further purification.

15 (2) A solution of the compound obtained above in (1) in chloroform (100 mL) was cooled in an ice-bath and 1N

hydrochloric acid (97 mL, 97 mmol) and sodium sulfite (4.5 g, 65 mmol) were added. The reaction mixture was
stirred for 40 minutes at the same temperature and then chloroform was added. The organic layer was separated
and dried over magnesium sulfate. After filtration, the filtrate was concentrated to afford a yellow oil (1 4 g), which
was used for the next reaction without further purification.

20 (3) To a solution of the compound (14 g, 32 mmol) obtained above in (2) in tetrahydrofuran (200 ml), was added

the compound (2.00 g, 1 0.6 mmol) of the reference example No. 3 at room temperature. The reaction mixture was
stirred for 2.5 hours at 95 °C. The reaction mixture was concentrated to leave a residue, which was purified by
column chromatography on silica gel (hexane-ethyl acetate, 1:1-1:2) to afford a light yellow crystal (8.0 g).
1 H-NMR(CDCI 3 )S:1. 01 (9H,s), 1.22-1 .37(1 H ! m),2.33-2.47(2H,m) ; 2.58-2.65(1 H,m),2. 81 (2H,t, J=6.3Hz),3. 45(1 H,t,

25 J=10Hz), 3.78(1H,dt),3.90(2H,t,J=6.3Hz),4.80(1H,dd),6.53(1H,s),6.82( 1 H,d,J=5.2Hz),7.30-7.47(8H ,m),7.53-

7.58(5H,m), 8.07(1 H,d,J=4.2Hz), 8.32(1 H,d,J=7.3Hz),1 2.0(1 H,s).

Reference Example No.6

30 [1137] The compound (8.0 g, 14 mmol) of the reference example No. 5 was dissolved in chloroform (50 mL). To this
solution, were added an imine (50 mL) prepared by the method wherein p-formaldehyde (71 .44 g, 2.38 mol) and tert-
butylamine (250 mL, 2.38 mol) were stirred at room temperature and one drop of concentrated sulfuric acid.
The reaction mixture was stirred for 3 days at 95°C. The reaction mixture was concentrated to leave a residue, which
was purified by column chromatography on silica gel (hexane-ethyl acetate, 3:1-1 :1-1 :2) to afford a colorless powder

35 (7.0 g).

1 H-NMR(CDCI 3 )5:0.98(9H,s), 0.98-1 .02(1 H,m),1 .28(9H,s), 2.20-2. 35(3H,m),2.80(2H,t,J=6.0Hz),3.33-3. 42(1 H,m),
3.64-3.73(1 H,m),3.86(2H,t,J=7.2Hz),4.67(1 H,d,J=1 2Hz), 4. 73-4.80(1 H,m),4.85(1 H, d,J=8.8Hz),5. 05-5.1 5(1 H,br),
5. 43-5.52(1 H,br), 6. 86(1 H,d,J=5.6Hz), 7.30-7. 41 (ehim), 7.49(1 H,dd),7.54-7.60(5H,m), 7. 76(2H,d,J=12Hz), 8. 23(1 H,d,
J=4.8Hz).

40

Reference Example No.7

[1138] The compound (2.00 g) of the reference example No. 6 was dissolved in tetrahydrofuran (20 mL). To the
mixture, was added a solution of tetra-n-butylammonium fluoride in tetrehydrofuran (1.0 M, 3.50 mL, 3.50 mmol) at

^5 room temperature. The reaction mixture was stirred for 1 hour at the same temperature and then water was added.
The reaction mixture was extracted with ethyl acetate. The organic layer was combined and washed with brine and
then dried over magnesium sulfate. After filtration, the filtrate was concentrated to result in the formation of crystal,
which was collected by filtration. The filtrate was concentrated again to leave a residue, which was purified by column
chromatography on silica gel (hexane-ethyl acetate, 1 :2-0:1 -chloroform-methanol, 50:1) to afford a crystal, which was

50 combined with the crystal collected above to provide the titled compound (700 mg).

1 H-NMR(CDCI 3 )S:1 .2-1 .35(1 H^)^ .30(9H,s) ! 2.20-2.40(3H ! m) ! 2.83(2H ! t ! J=6.6Hz),3.33-3.45(1 H,m),3.61 -3.74(1 H,
m),3.78(2H,t,J=6.6Hz),4.64-4.89(3H,m),5.07-5.20(1 H,m), 5.42-5. 55(1 H,m),6.91 (1 H,d, J=5.3Hz),7.45-7.59(2H,m),
7.74-7.81 (2H, m), 8. 28(1 H,d,J=5.3Hz).

238

EP 1 199 306 A1

Reference Example No.8
[1139]

5 (1) The compound (1 90 mg) of the reference example No. 7 was dissolved in chloroform (2 ml_). To the solution,

were added triphenylphosphine (1 46 mg, 0.56 mmol), diphenylphosphoryl azide (0.12 ml_, 0.56 mmol) and a so-
lution of diethyl azodicarboxylate in toluene (40%, 0.24 mL, 0.55 mmol) at room temperature. The reaction mixture
was stirred for 15 hours at the same temperature and water was added. The mixture was extracted with ethyl
acetate. The organic layer was combined and washed with water and brine and then dried over magnesium sulfate.

10 After filtration, the filtrate was concentrated to leave a residue, which was purified by thin layer chromatography

(chloroform-methanol, 1 9:1) to afford a light yellow amorphous (130 mg).

(2) The compound (1 30 mg) obtained above in (1 ) was dissolved in methanol-tetrahydrofuran (1:1) (2 mL). To the
solution, was added 10% palladium-carbon catalyst (130 mg) at room temperature. The reaction mixture was
stirred for 2 hours at the same temperature under an atomosphere of hydrogen. The insoluble material was filtered
15 through a celite pad and the filtrate was concentrated to leave a residue, which was purified by thin layer chroma-

tography (chloroform-methanol, 19:1) to afford the titled compound (32 mg) as a light yellow oil and the compound
(80 mg) of the working example No.1 09.

1 H-NMR(DMSO-d 6 )5: 1.23-1 .35(1 H,m), 1.29(9H,s), 2.21 -2.41 (3H,m),2.89(2H,brt),3.00(2H,brt),3.34-3.41 (1 H,m),
3.62-3.71 (1 H,m),4.65(1 H,d,J=1 2Hz),4.73-4.80(1 H,m), 4.83(1 H,d,J=12Hz), 5.00-5.20(1 H,br), 5.40-5.50(1 H,br),
20 6.81 (1 H,d,J=5.6Hz), 7.50(2H,t), 7.71 (2H,d,J=8.8Hz), 8.26(1 H,d, J=5.6Hz).

Reference Example No.9

[1140] The compound (800 mg) of the working example No. 81 was dissolved in pyridine (25 mL). To the solution,
25 was added methanesulfonyl chloride (0.263 ml, 3.40 mmol) at room temperature. The reaction mixture was stirred for
1 hour at the same temperature. The insoluble material was filtrated and the filtrate was concentrated to leave a residue,
which was dissolved in dimethylformamide. To the mixture, was added sodium azide (295 mg, 4.54 mmol) at room
temperature. The reaction mixture was stirred for 30 minutes at 80°C. The reaction mixture was cooled to room tem-
perature and water was added. The whole was extracted with ethyl acetate. The organic layer was washed with sat-
30 urated brine and then dried over magnesium sulfate. After filtration, the filtrate was concentrated to leave a residue,
which was purified by column chromatography on silica gel(hexane-ethyl acetate, 1 :2-0:1 ) to afford the titled compound
(265 mg).

1 H-NMR(CDCI 3 )5:1 .23-1 .37(1 H,m), 2. 33-2.51 (2H,m), 2.57-2. 67(1 H,m), 2. 90(2H,t,J=6.4Hz), 3.46(1 H,dt,J=1 OHz^Hz),
3.61 (2H,t,J=6.4Hz),3.77(1 H,q), 4. 77-4. 84(1 H,m),6.81 (1 H,s), 6.90(1 H,d,J=6.4Hz), 7.50(1 H,t,J=8.0Hz), 7. 57(1 H ,d,
35 J=4.8Hz),8. 1 7(1 H,d,J=4. 8Hz),8. 34(1 H,d, J=7.2Hz),8. 76(1 H,s).

Reference Example No. 10

[1141]

40

(1) The solution of p-nitrobenzenesulfonyl chloride (5.00 g, 22.6 mmol) in chloroform (50 mL) was cooled in an
ice-bath. To this, were added triethylamine (4.72 ml, 33.8 mmol) and 2,4-dimethoxybenzylamine (5.05 g, 30.1
mmol). The reaction mixture was stirred for 1 hour at room temperature and water was added. The whole was
extracted with ethyl acetate. The organic layer was combined and washed with 1N hydrochloric acid, saturated

45 aqueous sodium bicarbonate and brine in turn, and then dried over magnesium sulfate. After filtration, the filtrate

was concentrated to leave a crude product, which was used for the next reaction without further purification.

(2) The compound (1 .12 g) obtained above in (1 ) and the compound (1 .00 g) of the reference example No. 7 were
dissolved in chloroform (1 OmL). To the solution, were added triphenylphosphine (758 mg, 2.89 mmol) and asolution
of diethylazodicarboxylate in toluene (40%, 1 .26 mL, 2.89 mmol) at room temperature.

50 The reaction mixture was stirred for 1 5 hours at the same temperature. The mixture was concentrated to leave a

residue, which was purified by column chromatography on silica gel(hexane-ethyl acetate, 1:2-1:4) to afford a
yellow amorphous (1 .54 g).

1 H-NMR(CDCI 3 )5:1 .20-1 .40(1 H,m), 1 .30(9H,s), 2.20-2. 43(3H,m), 2.74(2H,t,J=7.6Hz),3.33-3.45(3H,m),3.61 (3H,
s),3.67-3.73(1H,m),3.73(3H,s) : 4.36(2H,s), 4.66(1 H,d,J=1 2Hz), 4.71 -4.80(1 H,m), 4.84(1 H,d,J=1 2Hz), 6.29(1H,d,
55 J=4.0Hz), 6.40(1 H,dd, J=8.0Hz, 4.0), 6.73(1 H,d,J=4.0Hz), 7.1 6(1 H,d,J=8.0Hz), 7.43-7.57(3H,m), 7.67(2H,t), 7.77

(1H,d,J=8.0Hz), 7.80(2H,d,J=8.0Hz) ,8.1 9-8.22(3H,m).

239

EP 1 199 306 A1

Reference Example No. 11

[1142] The compound (750 mg) of the reference example No. 10 was dissolved in dimethylformamide (7.5 mL). To the
solution, were added sodium carbonate (290 mg, 2.74 mmol) and thiophenol (0.120 ml, 1.17 mmol) at room temperature.
5 The reaction mixture was stirred for 4 days at room temperature. The insoluble material was filtrated and the filtrate was
concentrated to leave a residue, which was purified by column chromatography on silica gel (chloroform-methanol, 50:
1 -9:1-4:1) to afford a light yellow amorphous (350 mg).

1 H-NMR(CDCI 3 )5:1.30(10H,s),2.10-2.37(3H ; m),2.75-2.90(4H,m), 3.34-3.43(1 H,m),3. 73-3. 77(9H,m),4.67(1 H,d,J=9.6Hz),
4.77(1 H ; dd),4.85(1 H,d,J=9.6Hz),5. 05-5.1 5(1 H,br),5.40-5.50(1 H,br),6.39(2H,d,J=8.0Hz),6.87(1 H,d,J=6.4Hz),7-09(1 H,d
10 d),7.47-7.57(2H,m),7.75(2H,d,J=6.4Hz),8.25(1H,d,J=4.8Hz).

Formulation Examples of the Invention

[1143] The compound of the present invention will be described in more detail hereinunder, with formulation exam-
*s pies, which, however, are to concretely demonstrate the invention but not to restrict the scope of the invention.

Formulation Example No.1

[1144] Compound of working example No. 131 45 parts by weight dimagnesium oxide 15 parts by weight and
20 Lactose 75 parts by weight

were mixed and homogenized to make a pulverulent or subtle granular powder under 350 ujti. The powder was putted
into capsules.

Formulation Example No.2

25

[1145] Compound of working example No. 131 45 parts by weight, starch 15 parts by weight,
Lactose 1 6 parts by weight,
crystallinity cellulose 21 parts by weight,
polyvinylalcohol 3 parts by weight and
30 distilled water 30 parts by weight

were mixed and homogenized, and made parvules by crushing and dried. It was then screened to make granules in
size of 141 0-177u.m.

Formulation Example No.3

35

[1146] Granules which were made by the same method described in the formation example No.2, were mixed with
calcium stearate in ratio of 96:4(parts by weight). The mixture was pressed and mould to make tablets with a diameter
of 1 0 mm.

40 Formulation Example No.4

[1 1 47] Granules which were made by the method described in the formation example No.2 were mixed with crystal-
linity cellulose and calcium stearate in ratio of 90:1 0:3(parts by weight). The mixture was pressed and mould to make
tablets with a diameter of 8 mm. A suspension of syrup gelatin and precipitated calcium carbonate was used to make
45 sugar-coated tablets.

Formulation Example No.5

[1148] Compound of working example No. 131 0.6 parts by weight, non-ionic surfactant 2.4 parts by weight and
50 physiological salt solution 97 parts by weight were warmed for mixing and put into ampoules and sterilized to make
injections.

Industrial Applicability

55 [1149] Accordingto the present invention, thecompounds of the present invention have excellent activity of inhibiting
the growth of the tumor cells, thus this invention is to provide Cdk4 and/or Cdk6 inhibitor for treating malignant tumor.
According to the present invention, the compounds of the present invention have excellent activity of inhibiting the
growth of the tumor cells, thus this invention is to provide novel Cdk4 and/or Cdk6 inhibitor for treating malignant tumor.

240

EP 1 199 306 A1

Claims

1 . A compound of Formula (I) and pharmaceutical^ acceptable salts thereof:

Formula ( I )

HN

o

H

(I)

, wherein: Ar is a nitrogen-containing heteroaromatic ring group selected from a set of groups consisting of a pyridyl
group, a pyrimidinyl group, a pyradinyl group, a pyridazinyl group, a thiazolyl group, an isothiazolyl group, an
oxazolyl group, an isoxazolyl group, a pyrazolyl group, a pyrrolyl group, an imidazolyl group, an indolyl group, an
isoindolyl group, a quinolyl group, an isoquinolyl group, a benzothiazolyl group, and a benzoxazolyl group, which:

1) may be substituted with one to three of the same or different substituent(s) selected from a set of groups
consisting of a lower alkyl group, a hydroxyl group, a cyano group, halogen atoms, a nitro group, a carboxyl
group, a carbamoyl group, a formyl group, a lower alkanoyl group, a lower alkanoyloxy group, a hydroxy lower
alkyl group, a cyano lower alkyl group, a halo lower alkyl group, a carboxy lower alkyl group, a carbamoyl
lower alkyl group, lower alkoxy group, a lower alkoxycarbonyl group, lower alkoxycarbonylamino group, a
lower alkoxycarbonylamino lower alkyl group, a lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group,
a carbamoyloxy group, a lower alkylcarbamoyloxy group, a di-lower alkylcarbamoyloxy group, an amino group,
a lower alkylamino group, a di-lower alkylamino group, a tri-lower alkylammonio group, an amino lower alkyl
group, a lower alkylamino lower alkyl group, a di-lower alkylamino lower alkyl group, a tri-lower alkylammonio
lower alkyl group, a lower alkanoylamino group, an aroylamino group, a lower alkanoylamidino lower alkyl
group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a hydroxyimino
group and a lower alkoxyimino group, or groups represented by a formula Y 1 -Wi-Y 2 -R p (wherein: R p is any
of a hydrogen atom, or a lower alkyl group, a lower alkenyl group or a lower alkynyl group which may be
substituted with one to three of said substituent(s), oracyclo lower alkyl group, an aryl group, a heteroaromatic
ring group selected from a set of groups consisting of an imidazolyl group, an isoxazolyl group, an isoquinolyl
group, an isoindolyl group, an indazolyl group, an indolyl group, an indolizinyl group, an isothiazolyl group, an
ethylenedioxyphenyl group, an oxazolyl group, a pyridyl group, a pyradinyl group, a pyrimidinyl group, a pyri-
dazinyl group, a pyrazolyl group, a quinoxalinyl group, a quinolyl group, a dihydroisoindolyl group, a dihydroin-
dolyl group, a thionaphthenyl group, a naphthyridinyl group, a phenazinyl group, a benzoimidazolyl group, a
benzoxazolyl group, a benzothiazolyl group, a benzotriazolyl group, a benzofuranyl group, a thiazolyl group,
a thiadiazolyl group, a thienyl group, a pyrrolyl group, a furyl group, a furazanyl group, a triazolyl group, a
benzodioxanyl group and a methylenedioxyphenyl group, or an aliphatic heterocyclic group selected from a
set of groups consisting of an isoxazolinyl group, an isoxazolidinyl group, a tetrahydropyridyl group, an imida-
zolidinyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a piperazinyl group, a piperidinyl group,
a pyrrolidinyl group, pyrrolinyl group, a morpholino group, a tetrahydroquinolinyl group and a tetrahydroiso-
quinolinyl group, each of which cyclic group may be substituted with one to three of said substituent(s) or,
furthermore, may have a bicyclic or tricyclic fused ring of a partial structure selected from a set of groups
consisting of:

; W-| is a single bond, an oxygen atom, a sulfur atom, SO, S0 2 , NR q , S0 2 NR q , N(R q )S0 2 NR r , N(R q )S0 2 , CH
(OR q ), CONR q , N(R q )CO, N(R q )CONR r , N(R q )COO, N(R q )CSO, N(R q )COS, C(R q )=CR r , C=C, CO, OS, OC
(O), OC(0)NR q , OC(S)NR q , SC(O), SC(0)NR q and C(0)0 (wherein: R q and R r are each either a substituent

and

241

EP 1 199 306 A1

selected from a set of groups consisting of (i) a hydrogen atom, (ii) a substituent selected from a set of groups
consisting of a lower alkyl group, a cyclo lower alkyl group, a hydroxyl group, a cyano group, halogen atoms,
a nitro group, a carboxyl group, a carbamoyl group, a formyl group, a lower alkanoyl group, a lower alkanoyloxy
group, a hydroxy lower alkyl group, a cyano lower alkyl group, a halo lower alkyl group, a carboxy lower alkyl
group, a carbamoyl lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower alkoxycar-
bonylamino group, a lower alkoxycarbonylamino lower alkyl group, a lower alkylcarbamoyl group, a di-lower
alkylcarbamoyl group, a carbamoyloxy group, a lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy
group, an amino group, a lower alkylamino group, a di-lower alkylamino group, atri-lower alkylammonio group,
an amino lower alkyl group, a lower alkylamino lower alkyl group, a di-lower alkylamino lower alkyl group, a
tri-lower alkylammonio lower alkyl group, a lower alkanoylamino group, an aroylamino group, a lower alkanoy-
lamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino
group, a hydroxyimino group and a lower alkoxyimino group, or (iii) a lower alkyl group, an aryl group or an
aralkyl group which may be substituted with one to three of said substituent(s).); Y-| and Y 2 are each, the same
or different, a single bond or a straight-chain or branched lower alkylene group which may have any of said
bicyclic or tricyclic fused ring);

2) may have a five- to seven-membered fused ring selected from a set of groups consisting of:

which may be formed together with the carbon atom of said nitrogen-containing heteroaromatic cyclic group,
on which the substituent, which is selected from a set of groups consisting of a lower alkyl group, a lower
alkanoyl group, a lower alkanoyloxy group, a hydroxy lower alkyl group, a cyano lower alkyl group, a halo
lower alkyl group, a carboxy lower alkyl group, a carbamoyl lower alkyl group, lower alkoxy group, a lower
alkoxycarbonyl group, lower alkoxycarbonylamino group, a lower alkoxycarbonylamino lower alkyl group, a
lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group, a carbamoyloxy group, a lower alkylcarbamoy-
loxy group, di-lower alkylcarbamoyloxy group, an amino group, a lower alkylamino group, a di-lower alkylamino
group, a tri-lower alkylammonio group, an amino lower alkyl group, a lower alkylamino lower alkyl group, a di-
lower alkylamino lower alkyl group, a tri-lower alkylammonio lower alkyl group, a lower alkanoylamino group,
an aroylamino group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group,
and a lower alkanoylamidino lower alkyl group (hereinafter indicated as ring-substituent) stands, the carbon
atom next to said carbon atom, and a carbon atom, an oxygen atom and/or a nitrogen atom on said ring-
substituent;
or,

3) may have a five- to seven-membered ring selected from a set of groups consisting of:

which may be formed together with the carbon atom of said nitrogen-containing heteroaromatic group on which

242

EP 1 199 306 A1

a substituent represented by the formula Yi-Wi-Y 2 -R p (wherein:

Y-|, W-|, Y 2 and R p have the same meanings as stated above) stands, the carbon atom next to said carbon

atom, and a carbon atom, an oxygen atom and/or a nitrogen atom on said ring-substituent.

; X and Z are each, the same or different, a carbon atom or a nitrogen atom, or being taken together with R 1

5 or R 2 and/or R 3 which may exist on X or Z, form a CH or a nitrogen atom; Y is CO, SO or S0 2 ; R-| is any of a

hydrogen atom or a substituent represented by a formula Y 3 -W 2 -Y 4 -R s (wherein: R s is any of a hydrogen atom
or a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cyclo lower alkyl group, an aryl group,
and a heteroaromatic ring group selected from a set of groups consisting of an imidazolyl group, an isoxazolyl
group, an isoquinolyl group, an isoindolyl group, an indazolyl group, an indolyl group, an indolizinyl group, an

10 isothiazolyl group, an ethylenedioxyphenyl group, an oxazolyl group, a pyridyl group, a pyradinyl group, a

pyrimidinyl group, a pyridazinyl group, a pyrazolyl group, a quinoxalinyl group, a quinolyl group, a dihydroi-
soindolyl group, a dihydroindolyl group, a thionaphthenyl group, a naphthyridinyl group, a phenazinyl group,
a benzoimidazolyl group, a benzoxazolyl group, a benzothiazolyl group, a benzotriazolyl group, a benzof uranyl
group, athiazolyl group, athiadiazolyl group, athienyl group, a pyrrolyl group, afuryl group, afurazanyl group,

15 a triazolyl group, a benzodioxanyl group and a methylenedioxyphenyl group, or an aliphatic heterocyclic group

selected from a set of groups consisting of an isoxazolinyl group, an isoxazolidinyl group, a tetra hydro pyridyl
group, an imidazolidinyl group, a tetrahydrof uranyl group, a piperazinyl group, a piperidinyl group, a pyrrolidinyl
group, pyrrolinyl group, a morpholino group, a tetrahydroquinolinyl group and a tetrahydroisoquinolinyl group,
all of which may be substituted with one to three of said substituent(s); W 2 is a single bond, an oxygen atom,

20 a sulfur atom, SO, S0 2 , NR t , S0 2 NR t , N(R t )S0 2 NR u ,N(R t )S0 2 , CH(OR t ), CONR t , N(R t )CO, N(R t )CONR u , N

(R t )COO, N(R t )CSO, N(R t )COS, C(R v )=CR r , C=C, CO, CS, OC(O), OC(0)NR t , OC(S)NR t , SC(O), SC(0)NR t
and C(0)0 (wherein: R t and R u are each a hydrogen atom or a substituent selected from a set of groups
consisting of a lower alkyl group, a hydroxy group, a cyano group, halogen atoms, a nitro group, a carboxyl
group, a carbamoyl group, a formyl group, a lower alkanoyl group, a lower alkanoyloxy group, a hydroxy lower

25 alkyl group, a cyano lower alkyl group, a halo lower alkyl group, a carboxy lower alkyl group, a carbamoyl

lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower alkoxycarbonylamino group, a
lower alkoxycarbonylamino lower alkyl group, a lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group,
a carbamoyloxy group, a lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, an amino group,
a lower alkylamino group, a di-lower alkylamino group, a tri-lower alkylammonio group, an amino lower alkyl

30 group, a lower alkylamino lower alkyl group, a di-lower alkylamino lower alkyl group, a tri-lower alkylammonio

lower alkyl group, a lower alkanoylamino group, an aroylamino group, a lower alkanoylamidino lower alkyl
group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a hydroxyimino
group and a lower alkoxyimino group, or a lower alkyl group, an aryl group or an aralkyl group which may be
substituted with one to three of said substituent(s)); Y 3 and Y 4 are each, the same or different, a single bond

35 or a straight-chain or branched lower alkylene group), or R 1 is an lower alkyl group which may be substituted

with one to three of the same or different substituent(s) selected from a set of groups consisting of a lower
alkyl group, a hydroxyl group, a cyano group, halogen atoms, a nitro group, a carboxyl group, a carbamoyl
group, a formyl group, a lower alkanoyl group, a lower alkanoyloxy group, a hydroxy lower alkyl group, a cyano
lower alkyl group, a halo lower alkyl group, a carboxy lower alkyl group, a carbamoyl lower alkyl group, lower

40 alkoxy group, a lower alkoxycarbonyl group, lower alkoxycarbonylamino group, a lower alkoxycarbonylamino

lower alkyl group, a lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group, a carbamoyloxy group, a
lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, an amino group, a lower alkylamino group,
a di-lower alkylamino group, a tri-lower alkylammonio group, an amino lower alkyl group, a lower alkylamino
lower alkyl group, a di-lower alkylamino lower alkyl group, a tri-lower alkylammonio lower alkyl group, a lower

45 alkanoylamino group, an aroylamino group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl

group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a hydroxyimino group and a lower alkox-
yimino group, or a substituent selected from groups represented by the formula Y 3 -W 2 -Y 4 -R s (wherein: R s ,
W 2 , Y 3 and Y 4 have the same meanings as stated above), or R 1 forms a nitrogen atom together with X.); R 2
and R 3 are each independently, the same or different, a hydrogen atom, a hydroxy group, a lower alkyl group,

50 a lower alkoxy group, or a substituent represented by the formula Y 3 -W 2 -Y 4 -R s ( wherein: R s , W 2 , Y 3 and Y 4

have the same meanings as stated above), or one of R 2 or R 3 forms, together with R 1 and X, a saturated five-
to eight-membered cyclic group selected from sets of groups consisting of (a) and (b):

55

243

EP 1 199 306 A1

and

and another one of R 2 or R 3 binds to a carbon atom or a nitrogen atom on the ring, or to a carbon atom, an
oxygen atom and/or nitrogen atom on said ring-substituent of said ring to form a five- to seven-membered
ring, or R 2 and R 3 are combined to form a spiro cyclo lower alkyl group, or R 2 and R 3 are combined, together
with Z on which they exist to form an oxo (keto, or carbonyl) group, or R 2 and R 3 form, together with Z, Ri and
X, on which they stand, a saturated or an unsaturated five- to eight membered cyclic group which may be
selected from sets of groups of (a) and (b):

and

, which may contain one or more kinds of hetero atom(s) selected from a group of a nitrogen atom, an oxygen
atom and a sulfur atom, and which may be fused with any of a cyclo lower alkyl group, an aryl group, a het-
eroaromatic ring group selected from a set of groups consisting of an imidazolyl group, an isoxazolyl group,
an isoquinolyl group, an isoindolyl group, an indazolyl group, an indolyl group, an indolydinyl group, an isothi-
azolyl group, an ethylenedioxyphenyl group, an oxazolyl group, a pyridyl group, a pyradinyl group, a pyrimidinyl
group, a pyridazinyl group, a pyrazolyl group, a quinoxalinyl group, a quinolyl group, a dihydroisoindolyl group,
a dihydroindolyl group, athionaphthenyl group, a naphthyridinyl group, a phenazinyl group, a benzoimidazolyl
group, a benzoxazolyl group, a benzothiazolyl group, a benzotriazolyl group, a benzofuranyl group, a thiazolyl
group, a thiadiazolyl group, a thienyl group, a pyrrolyl group, afuryl group, afurazanyl group, atriazolyl group,
a benzodioxanyl group and a methylenedioxyphenyl group, or an aliphatic heterocyclic group(s) selected from

244

EP 1 199 306 A1

a set of groups consisting of an isoxazolinyl group, an isoxazolidinyl group, a tetrahydropyridyl group, an
imidazolidinyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a piperazinyl group, a piperidinyl
group, a pyrrolidinyl group, pyrrolinyl group, a morpholino group, a tetrahydroquinolinyl group and a tetrahy-
droisoquinolinyl group, which may be substituted with one to three of the same or different substituent(s)
selected from a set of groups consisting of a lower alkyl group, a spiro cyclo lower alkyl group which may be
substituted, a hydroxyl group, a cyano group, halogen atoms, a nitro group, a carboxyl group, a carbamoyl
group, aformyl group, a lower alkanoyl group, a lower alkanoyloxy group, a hydroxy lower alkyl group, a cyano
lower alkyl group, a halo lower alkyl group, a carboxy lower alkyl group, a carbamoyl lower alkyl group, lower
alkoxy group, a lower alkoxycarbonyl group, lower alkoxycarbonylamino group, a lower alkoxycarbonylamino
lower alkyl group, a lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group, a carbamoyloxy group, a
lower alkyl carbamoyloxy group, di-lower alkylcarbamoyloxy group, an amino group, a lower alkylamino group,
a di-lower alkylamino group, a tri-lower alkylammonio group, an amino lower alkyl group, a lower alkylamino
lower alkyl group, a di-lower alkylamino lower alkyl group, a tri-lower alkylammonio lower alkyl group, a lower
alkanoylamino group, an aroylamino group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl
group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a hydroxyimino group and a lower alkox-
yimino group, and a substituent selected from groups represented by the formula Y-i-W^Yg-Rp (wherein: R p ,
Y 1 and Y 2 have the same meanings as stated above); R 4 and R 5 are each, the same or different, a
hydrogen atom, halogen atoms, a hydroxy group, an amino group, or a substituent represented by the formula
Y 3 -W 2 -Y 4 -R s (wherein: R s , W 2 , Y 3 and Y 4 have the same meanings as stated above), or any of a lower alkyl
group, an aryl group or an aralkyl group which may be substituted with one to three of the same or different
substituent(s) selected from both a set of groups consisting of a lower alkyl group, a cyano group, a nitro
group, a carboxyl group, a carbamoyl group, a formyl group, a lower alkanoyl group, a lower alkanoyloxy
group, a hydroxy lower alkyl group, a cyano lower alkyl group, a halo lower alkyl group, a carboxy lower alkyl
group, a carbamoyl lower alkyl group, lower alkoxy group, a lower alkoxycarbonyl group, lower alkoxycarbo-
nylamino group, a lower alkoxycarbonylamino lower alkyl group, a lower alkylcarbamoyl group, a di-lower
alkylcarbamoyl group, a carbamoyloxy group, a lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy
group, an amino group, a lower alkylamino group, a di-lower alkylamino group, a tri-lower alkylammonio group,
an amino lower alkyl group, a lower alkylamino lower alkyl group, a di-lower alkylamino lower alkyl group, a
tri-lower alkylammonio lower alkyl group, a lower alkanoylamino group, an aroylamino group, a lower alkanoy-
lamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino
group, a hydroxyimino group and a lower alkoxyimino group, and groups represented by the formula Y 3 -W 2 -
Y 4 -R s (wherein: R s , W 2 , Y 3 and Y 4 have the same meanings as stated above); and the formula™ represents
either a single bond or a double bond.

A compound according to claim 1, having a structure of Formula (l-a), and pharmaceutically acceptable salts
thereof:

, wherein: Ar a is a nitrogen-containing hetero aromatic ring group selected from a set of groups consisting of a
pyridyl group, a pyrimidinyl group, a pyradinyl group, a pyridazinyl group, a thiazolyl group, a pyrazolyl group, and
an imidazolyl group, and said nitrogen-containing heteroaromatic ring group

1 ') may be substituted with one to three of the same or different substituent(s) selected from a set of groups
consisting of a lower alkyl group, a hydroxyl group, halogen atoms, a formyl group, a lower alkanoyl group, a
lower alkanoyloxy group, a hydroxy lower alkyl group, a halo lower alkyl group, a carbamoyl lower alkyl group,
lower alkoxy group, a lower alkoxycarbonyl group, lower alkoxycarbonylamino group, a lower alkoxycarbo-
nylamino lower alkyl group, a lower alkylcarbamoyl group, a lower alkylcarbamoyloxy group, an amino group,
a lower alkylamino group, a di-lower alkylamino group, an amino lower alkyl group, a lower alkylamino lower

Formula (I -a)

R 4a R 5a

245

EP 1 199 306 A1

alkyl group, a di-lower alkylamino lower alkyl group, a lower alkanoylamino group, an aroylamino group, a
lower alkylsulfonylamino group, or groups represented by a formula Y 1a -W 1a -Y 2a -R pa (wherein: R pa is any of
a hydrogen atom or a lower alkyl group, a lower alkenyl group or a lower alkynyl group which may be substituted
with one to three of said substituent(s), oracyclo lower alkyl group, an aryl group, a heteroaromatic ring group
selected from a set of groups consisting of an imidazolyl group, an isoxazolyl group, an isoquinolyl group, an
indolyl group, an ethylenedioxyphenyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a pyra-
zolyl group, a quinolyl group, a benzoimidazolyl group, a thiazolyl group, a thienyl group, and a triazolyl group,
or an aliphatic heterocyclic group(s) selected from a set of groups consisting of an isoxazolinyl group, an
isoxazolidinyl group, a tetra hydro pyridyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a piper-
azinyl group, a piperidinyl group, a pyrrolidinyl group, a morpholino group, and a tetrahydroisoquinolinyl group,
any of which cyclic groups may be substituted with one to three of said substituents, or, furthermore, may have
a bicyclic or tricyclic fused ring which contains a partial structure selected from a set of groups consisting of:

o.o o

and

; W 1a is an oxygen atom, a sulfur atom, NR qa , S0 2 NR qa , N(R qa )S0 2 , CONR qa , N(R qa )CO ; N(R qa )COO, C
(R qa )=CR ra , OC(O), OC(0)NR qa , or C(0)0 (wherein: R qa and R ra are each, a hydrogen atom or a substituent
selected from a set of groups consisting of a lower alkyl group, a cyclo lower alkyl group, a hydroxyl group,
halogen atoms, a formyl group, a lower alkanoyloxy group, a hydroxy lower alkyl-group, a halo lower alkyl
group, a carbamoyl lower alkyl group, lower alkoxy group, a lower alkoxycarbonyl group, a lower alkoxycarb-
onylamino group, a lower alkoxycarbonylamino lower alkyl group, a lower alkylcarbamoyl group, a lower alkyl-
carbamoyloxy group, an amino group, a lower alkylamino group, a di-lower alkylamino group, an amino lower
alkyl group, a lower alkylamino lower alkyl group, a di-lower alkylamino lower alkyl group, a lower alkanoylami-
no group, an aroylamino group, and a lower alkylsulfonylamino group, or a lower alkyl group, an aryl group or
an aralkyl group which may be substituted with one to three of said substituent(s)); Y 1a and Y 2a are each, the
same or different, a single bond or a straight-chain or branched lower alkylene group which may have a bicyclic
or tricyclic fused ring.);

2') may form a five- to six-membered ring selected from a set of groups consisting of:

together with a carbon atom on said nitrogen-containing heteroaromatic ring group, on which a substituent
selected from a set of groups consisting of a lower alkyl group, a lower alkanoyloxy group, a hydroxy lower
alkyl group, a halo lower alkyl group, a carbamoyl lower alkyl group, a lower alkoxy group, a lower alkoxycar-
bonyl group, a lower alkoxycarbonylamino group, a lower alkoxycarbonylamino lower alkyl group, a lower
alkylcarbamoyl group, a lower alkylcarbamoyloxy group, a lower alkylamino group, di-lower alkylamino group,
an amino lower alkyl group, a lower alkylamino lower alkyl group, di-lower alkylamino lower alkyl group, a
lower alkanoylamino group, and an aroylamino group exists, the carbon atom next to said carbon atom, and
a carbon atom, an oxygen atom and/or a nitrogen atom, each of which exists in said ring-substituent(s);
or,

3') may form a five- to six-membered ring selected from a set of groups consisting of:

0.6.0-0

and

together with a carbon atom on said nitrogen-containing heteroaromatic ring group, on which a substituent
represented by the formula Y 1a -W 1a -Y 2a -R pa (wherein: Y 1a , W 1a , Y 2a and R pa have the same meanings as

246

EP 1 199 306 A1

stated above) stands, the carbon atom next to said carbon atom, and a carbon atom, an oxygen atom and/or
a nitrogen atom in said ring-substituent(s); X a and Z a are each, the same or different, a carbon atom or a
nitrogen atom, or optionally being taken together with R 1a or R 2a and/or R 3a on them form a CH or a nitrogen
atom; Y a is a CO, SO or S0 2 . R 1a is a hydrogen atom or a substituent represented by a formula Y 3a -W 2a -Y 4a -
R sa (wherein: R sa is a hydrogen atom or a lower alkyl group, a lower alkenyl group, a cyclo lower alkyl group,
an aryl group ; or a heteroaromatic ring group selected from a group consisting of an indolyl group, or an
aliphatic heterocyclic group selected from a group of a tetrahydropyridyl group, a piperadinyl group, a pipe-
ridinyl group, a pyrrolidinyl group and a morpholino group, all of which groups may be substituted with one to
three of the same or different said substituent(s); W 2a is a single bond, NR ta , CH(OR ta ), CONR ta , N(R ta )CO,
N(R ta )COO, OC(0)NR ta or C(0)0 (wherein: R ta is a hydrogen atom, a lower alkyl group, an aryl group or an
aralkyl group which may be substituted with one to three of said substituent(s)); Y 3a and Y 4a are each, the
same or different, a single bond, or a straight-chain or branched lower alkylene group); or R 1 is a lower alkyl
group which may be substituted with one to three substituent(s) selected from both a set of groups consisting
of a lower alkyl group, a hydroxyl group, a carbamoyl group ; a lower alkanoyloxy group, a hydroxy lower alkyl
group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower alkoxycarbonylamino group, a lower alkox-
ycarbonylamino lower alkyl group, a lower alkylcarbamoyl group, a di-loweralkylcarbamoyl group, acarbamoy-
loxy group, a lower alkylcarbamoyloxy group, a lower alkylamino group, a di-lower alkylamino group, an amino
lower alkyl group, a lower alkylamino lower alkyl group, a di-lower alkylamino lower alkyl group, a lower al-
kanoylamino group, and an aroylamino group, and groups represented by the formula Y 3a -W 2a -Y 4a -R sa
(wherein: R sa , W 2a , Y 3a and Y 4a have the same meanings as stated above), orform a nitrogen atom, together
with X; R 2a and R 3a are each independently, the same or different, a hydrogen atom, or a substituent of a
hydroxy group, a lower alkyl group, a lower alkoxy group, or the one represented by the formula Y 3a -W 2a -Y 4a -
R sa (wherein: R sa , W 2a , Y 3a and Y 4a have the same meanings as stated above), or any one of R 2a or R 3a
forms, together with R 1a and X a , a saturated five- to eight-membered cyclic group selected from a set of groups
consisting of (a-1) and (b-1),

and

and the other one binds to a carbon atom or a nitrogen atom on the ring, or to a carbon atom, an oxygen atom
and/or nitrogen atom on said ring-substituent to form a five- to seven-membered ring, or R 2a and R 3a are
combined to form a spiro cyclo lower alkyl group, or R 2a and R 3a are combined with Z on which they stand to
form an oxo (a keto, or carbonyl) group, or R 2a and R 3a form, together with Z a on which they stand, R 1a and
X a , a saturated or an unsaturated five- to eight membered cyclic group which may be selected from sets of
groups of (a-1) and (a-2):

(a-1)

247

EP 1 199 306 A1

and

(a-2)

and

which may have one or more kinds of hetero atom(s), and which may be substituted with one to three of the
same or different substituent(s) selected both from a set of groups consisting of a lower alkyl group, a spiro
cyclo lower alkyl group which may be substituted, a hydroxy group, a hydroxy lower alkyl group, lower alkoxy
group, a lower alkoxycarbonyl group, a lower alkoxycarbonylamino group, a lower alkoxycarbonylamino lower
alkyl group, a lower alkylcarbamoyl group, a lower alkylcarbamoyloxy group, a lower alkylamino group, a di-
loweralkylamino group, an amino loweralkyl group, a lower alkylamino loweralkyl group, a di-lower alkylamino
lower alkyl group, a lower alkanoylamino group and an aroylamino group, and groups represented by the
formula Y 1a -W 1a -Y 2a -R pa (wherein: R pa , W 1a , Y 1a and Y 2a have the same meanings as stated above), and,
furthermore, which may be fused with a cyclo lower alkyl group, an aryl group, a heteroaromatic ring group
selected from a group of a pyridyl group and a pyrazolyl group, and an aliphatic heterocyclic group selected
from a group of piperidinyl group and a pyrrolidinyl group; R 4a and R 5a are each, the same or different, a
hydrogen atom or a substituent consisting of halogen atoms, a hydroxy group, an amino group, or the one
represented by the formula Y 3a -W 2a -Y 4a -R sa (wherein: R sa , W 2a , Y 3a and Y 4a have the same meanings as
stated above), or a lower alkyl group, an aryl group or an aralkyl group, each of which may be substituted with
one to three of the same or different substituent(s) selected from both a set of groups consisting of a lower
alkyl group, a hydroxy lower alkyl group, a halo lower alkyl group, a lower alkoxycarbonylamino group, a lower
alkoxycarbonylamino lower alkyl group, a lower alkylcarbamoyl group, a lower alkylamino group, a lower
alkylamino lower alkyl group, a lower alkanoylamino group, and an aroylamino group, and groups represented
by the formula Y 3a -W 2a -Y 4a -R sa (wherein: R sa , W 2a , Y 3a and Y^ have the same meanings as stated above);
and the formula ™ is a single bond or a double bond.

A compound according to claim 1 and 2, having a structure of Formula (l-b) and pharmaceutically acceptable salts
thereof,

wherein: Ar b is a nitrogen-containing heteroaromatic ring group selected from a set of groups comprising a
pyridyl group and a pyrazolyl group, which:

1") may be substituted with one to three substituent(s) selected from both a set of groups consisting of a
hydroxy group, halogen atoms, a lower alkanoyloxy group, a hydroxy lower alkyl group, a lower alkoxy group,
a lower alkoxycarbonyl group, an amino group, and a lower alkylamino lower alkyl group, and groups repre-
sented by a formula Y 1b -W 1b -Y 2b -Rpb (wherein: R pb is a hydrogen atom or a lower alkyl group, a lower alkenyl
group or a lower alkynyl group which may be substituted with one to three of said substituent(s), or a cyclo
lower alkyl group, an aryl group, a heteroaromatic ring group selected from a set of groups consisting of a
pyridyl group and a pyrazolyl group, or an aliphatic heterocyclic group selected from a set of groups consisting
of isoxazolinyl group, a tetra hydro pyridyl group, a piperadinyl group, a piperidinyl group, a pyrrolidinyl group,
a morpholino group and a tetrahydroisoquinolinyl group, each of which cyclic substituent groups may be sub-
stituted with one to three of said substituent(s) and, furthermore, may have a bicyclic or tricyclic fused ring,
which contains the partial structure of which is selected from a group consisting of:

Formula (I-b)

R{b R 2b

R 4b R 5b

248

EP 1 199 306 A1

and

; W 1b is NR qb! N(R qb )S0 2! CONR qb , N(R qb )CO, N(R qb )COO, OC(O), and C(0)0 (wherein: R qb and R rb is a
hydrogen atom, or a substituent selected from a set of groups consisting of a hydroxy group, halogen atoms,
a cyclo lower alkyl group, a lower alkanoyloxy group, a hydroxy lower alkyl group, a lower alkoxy group, a
lower alkoxycarbonyl group, an amino group, and a lower alkylamino lower alkyl group, or a lower alkyl group,
an aryl group or an aralkyl group, which may be substituted with one to three of said substituent(s)); Y 1b and
Y 2b are each, the same or different, a single bond or a straight-chain or branched lower alkylene group which
may have a said bicyclic or tricyclic fused ring);

2") may have a five- or six-membered ring selected from a group consisting of:

0,0,0,0

and

which is together with the ring carbon atom on which a substituent selected from a group consisting of a lower
alkanoyloxy group, a hydroxy lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group and a
lower alkylamino lower alkyl group stands, a carbon atom next to said carbon atom, and a carbon atom, an
oxygen atom and/or a nitrogen atom in said ring-substituent; or.
3") may form a five- or six-membered ring selected from a group consisting of:

O.6.O. 0

and

which is together with the ring-carbon atom on which a substituent represented by the formula Y 1b -W 1b -Y 2b -
R pb (wherein: Y 1b , W 1b , Y 2b and R pb have the same meanings as stated above) stands, a carbon atom next
to said carbon atom, and a carbon atom, an oxygen atom and/or a nitrogen atom in said ring-substituent; X b
and Z b are each, the same or different, a carbon atom or a nitrogen atom, orX b and Z b form a CH or a nitrogen
atom, being taken together with R 1b or R 2b and/or R 3b on them; Y b is a CO, SO or S0 2 ; R-| b is a hydrogen
atom or a substituent represented by a formula Y 3b -W 2b -Y 4b -R sb (wherein: R sb is a hydrogen atom or a lower
alkyl group, a cyclo lower alkyl group, and an aryl group, which may be substituted with one to three of said
substituent(s); W 2b is a single bond, N(R tb )COO or C(0)0 (wherein: R tb is a hydrogen atom or a lower alkyl
group, an aryl group or an aralkyl group which may be substituted with one to three of said substituent(s));
Y 3b and Y 4b are each, the same or different, a single bond, or a straight-chain or branched lower alkylene
group), or a lower alkyl group which may be substituted with one to three of the same or different substituent
(s) selected from a set of groups consisting of a hydroxy lower alkyl group and the one represented by the
formula Y 3b -W 2b -Y 4b -R sb (wherein: R sb , W 2b , Y 3b and Y 4b have the same meanings as stated above), orforms
a nitrogen atom, together with X; R 2b and R 3b are each independently, the same or different, a hydrogen atom,
a hydroxy group, a lower alkyl group, a lower alkoxy group, or a substituent represented by the formula Y 3b -
W 2b -Y 4b -R sb (wherein: R sb , W 2b , Y 3b and Y 4b have the same meanings as stated above), or either R 2b or R 3b
forms, together with R 1b and X b , a saturated five- to eight-membered cyclic group selected from sets of groups
of (b-1) and (b-2),

(b-1) . . ^

. , .0
N and N — '

249

EP 1 199 306 A1

and

(b-2, N f

\— J and O-l

and the other one binds to a carbon atom or a nitrogen atom on the ring, or to a carbon atom, an oxygen atom
and/or nitrogen atom on said ring-substituent to form a five- to seven-membered ring, or R 2b and R 3b are
combined to form a spiro cyclo lower alkyl group, or they (R 2b and R 3b ) are combined furthermore with Z on
which they stand to form an oxo (a keto, or carbonyl) group, or they (R 2b and R 3b ) form ; together with Z b on
which they stand, R 1b and X b , a saturated or an unsaturated five- to seven-membered cyclic group which may
be selected from sets of groups of (b-1) and (b-2):

N and

and

( b * 2 ) N N <5 N

o • o , {y o

1 — and u

which may either have one or more kinds of hetero atom(s) selected from a group of a nitrogen atom, an
oxygen atom and a sulfur atom, or which may be fused with a cyclo lower alkyl group, an aryl group and an
aliphatic heterocyclic group selected from a group of a piperidinyl group and a pyrrolidinyl group, all of which
cyclic groups may be substituted with one to three of the same or different substituent(s) selected both from
a set of groups consisting of a lower alkyl group, a spiro cyclo lower alkyl group which may be substituted, a
hydroxy lower alkyl group and a lower alkoxycarbonyl group, and groups represented by the formula Y 1b -W 1b -
Y 2b -R pb (wherein: R pb , W 1b , Y 1b and Y 2b have the same meanings as stated above);

R 4b and R 5b are each independently, the same or different, or a lower alkyl group, an aryl group or an aralkyl
group which may be substituted with one to three of the same or different substituent(s) selected from a set
of groups consisting of substituents comprising any of a hydrogen atom, halogen atoms or a substituent rep-
resented by the formula Y 3b -W 2b -Y 4b -R sb (wherein: R sb; W 2b , Y 3b and Y 4b have the same meanings as stated
above), or a substituent selected from a set of groups consisting of a lower alkyl group, a hydroxy lower alkyl
group, a halo lower alkyl group, a lower alkoxycarbonylamino group, a lower alkoxycarbonylamino lower alkyl
group, a lower alkylcarbamoyl group, a lower alkylamino group, a lower alkylamino lower alkyl group, a lower
alkanoylamino group, and an aroylamino group,; and the formula ™ means a single bond or a double bond.

A compound according to any one of claim 1 to claim 3, having a structure of Formula (l-p) and pharmaceutically
acceptable salts thereof,

Formula (I-p)

o

250

EP 1 199 306 A1

wherein: Ar p is a nitrogen-containing hetero aromatic ring group which may be substituted, X p is a carbon atom
(CH) or a nitrogen atom, R 1p is a hydrogen atom or a lower alkyl group which may be substituted, R 2p is a hydrogen
or an oxo group (which forms carbonyl group, together with the carbon atom on which it stands), or forms, together
with the carbon atom on which it stands, R 1p and X p , a saturated or an unsaturated five- or six-membered cyclic
group which may have one or more kinds of hetero atom(s) selected from a group of a nitrogen atom and a sulfur
atom or which may be substituted; R 4p and R 5p are each, the same of different, any of a hydrogen atom, halogen
atoms, a hydroxy group, an amino group or a lower alkyl group, an aryl group or an aralkyl group which may be
substituted.

A compound according to claim 1 , wherein the compound is N'-(pyrrolidino[2, 1 -b]isoindolin-4-on-8-yl)-N-(5-(2-oc-
tylaminomethyl)pyrazol-3-yl)urea, N'-(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)-N-(5-(2-methyl-4,4-dimethylpentyl-
aminomethyl)pyrazol-3-yl)urea, N'-(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)-N-(5-(5-methoxyindan-2-ylaminome-
thyl)pyrazol-3-yl)urea, N'-(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)-N-(5-(2-methylindan-2-ylaminomethyl)pyrazol-3-
yl)urea, N'-(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)-N-(5-(5-chloroindan-2-ylaminomethyl)pyrazol-3-yl)urea, N'-(pyr-
rolidino[2,1 -b]isoindolin-4-on-8-yl)-N-(5-(6-methylpyridin-2-yl)pyrazol-3-yl)urea, N'-(pyrrolidino[2,1 -b]isoindolin-
4-on-8-yl)-N-(5-(pyrrolidin-2-yl)pyrazol-3-yl)urea, N'-(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)-N-(5-(t-butylaminome-
thyl)pyrazol-3-yl)urea, N'-(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)-N-(5-(pyrazolo[5,4-b]pyridin-3-yl)urea, N'-(pyrro-
lidino[2,1 -b]isoindolin-4-on-8-yl)-N-(5-(1 -hydroxymethylcyclopentylaminomethyl)pyrazol-3-yl)urea, N'-(pyrrolidino
[2,1 -b]-4-oxoisoindolin-8-yl)-N-(5-(N-t-butyl-N-methyl-aminomethyl)pyrazol-3-yl)urea, N'-(pyrrolidino[2,1 -b]isoin-
dolin-4-on-8-yl)-N-(4-(N -benzyl- 1 ,2,5,6-tetrahydropyridin-4-yl)pyridin-2-yl)urea, N'-(pyrrolidino[2,1 -b]isoindolin-
4-on-8-yl)-N-(4-(N-benzyl-4-piperidyl)pyridin-2-yl)urea, N'-(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)-N-(4-(N-benzyl-
1 ,2,5,6-tetrahydropyridin-3-yl)pyridin-2-yl)urea, N'-(pyrrolidino[2,1-b]isoindolin-4-on-8-yl)-N-(4-(N-benzyl-3-pip-
eridyl)pyridin-2-yl)urea, N'-(pyrrolidino[2, 1 -b]-4-oxoisoindolin-8-yl)-N-(4-(1 ,2,5,6-tetrahydropyridin-3-yl)pyridin-

2- yl)urea, N'-(pyrrolidino[2, 1 -b]isoindolin-4-on-8-yl)-N-(4-(N-acetyl-3-piperidyl)pyridin-2-yl)urea, N'-(pyrrolidino
[2,1 -b]isoindolin-4-on-8-yl)-N-(piperidino[3,4-c]pyridin-5-yl)urea, N'-(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)-N-(pyr-
rolidino[3,4-c]pyridin-5-yl)urea, N'-(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)-N-(4-(cyclohexylaminoethyl)pyridin-2-yl)
urea, N'-(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)-N-(4-(N-cyclohexylpyrrolidin-3-yl)pyridin-2-yl)urea (compound
1 80), N'-(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)-N-(4-(N-benzylpyrrolidin-3-yl)pyridin-2-yl)urea, N'-(N-cyclopentyl-

3- methylisoindolin-1 -on-4-yl)-N-(pyridin-2-yl)urea, N'-(3-t-butylisoindolino[3,2-b]oxazolidin-4-on-8-yl)-N-(4-(N-
benzylpyrrolidin-3-yl)pyridin-2-yl)urea, N'-(2-methylisoindolino[3,2-b]perhydro-1 ,3-oxazin-5-on-9-yl)-N-(4-(N-ben-
zylpyrrolidin-3-yl)pyridin-2-yl)urea, or N'-(isoindolino[2,3-b]perhydro-1 ,4-methano-6, 1 1 a-benzoxazin-1 1 -on-7-yl)
-N-(pyridin-2-yl)urea.

A compound according to claim 1 , wherein the compound is N'-(pyrrolidino[2, 1 -b]isoindolin-4-on-8-yl)-N-(5-(2-oc-
tylaminomethyl)pyrazol-3-yl)urea, N'-(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)-N-(5-(2-methyl-4,4-dimethylpentyl-
aminomethyl)pyrazol-3-yl)urea, N'-(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)-N-(5-(5-methoxyindan-2-ylaminome-
thyl)pyrazol-3-yl)urea, N'-(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)-N-(5-(2-methylindan-2-ylaminomethyl)pyrazol-3-
yl)urea, N'-(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)-N-(5-(5-chloroindan-2-ylaminomethyl)pyrazol-3-yl)urea, N'-(pyr-
rolidino[2,1 -b]isoindolin-4-on-8-yl)-N-(4-(N-benzyl-1 ,2,5,6-tetrahydropyridin-4-yl)pyridin-2-yl)urea, N'-(pyrrolidino
[2,1 -b]isoindolin-4-on-8-yl)-N-(4-(N-benzyl-4-piperidyl)pyridin-2-yl)urea, N'-(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)
-N-(piperidino[3,4-c]pyridin-6-yl)urea, N'-(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)-N-(4-(N-cyclohexylpyrrolidin-3-yl)
pyridin-2-yl)urea, N'-(pyrrolidino[2,1 -b]isoindolin-4-on-8-yl)-N-(4-(N-benzylpyrrolidin-3-yl)pyridin-2-yl)urea, N'-(3-
t-butylisoindolino[3,2-b]oxazolidin-4-on-8-yl)-N-(4-(N-benzylpyrrolidin-3-yl)pyridin-2-yl)urea, N'-(2-methylisoin-
dolino[3,2-b]perhydro-1 ,3-oxazin-5-on-9-yl)-N-(4-(N-benzylpyrrolidin-3-yl)pyridin-2-yl)urea, or N'-(isoindolino[2,
3-b]perhydro-1 ,4-methano-6, 11 a-benzoxazin-1 1 -on-7-yl)-N-(pyridin-2-yl)urea.

A method of manufacturing a compouns of Formula (I) and pharmaceutically acceptable salts thereof character-
ized by reacting compounds of Formula (III) with a compound of Formula (IV):

251

EP 1 199 306 A1

10

Formula (III)

(in)

wherein: X and Z are each, the same or different, a carbon atom or a nitrogen atom, or a CH or a nitrogen atom,
together with R 10 or R 20 and/or R 30 which bind to X or Z; Y is a CO, SO or S0 2 ; R-io is a hydrogen atom or a
substituent represented by a formula Y 30 -W 20 -Y 40 -R s0 (wherein: R s0 is a hydrogen atom or a lower alkyl group, a

*s lower alkenyl group, a lower alkynyl group, a cyclo lower alkyl group, an aryl group, a heteroaromatic ring group

selected from a set of groups consisting of an imidazolyl group, an isoxazolyl group, an isoquinolyl group, an
isoindolyl group, an indazolyl group, an indolyl group, an indolydinyl group, an isothiazolyl group, an ethylenedi-
oxyphenyl group, an oxazolyl group, a pyridyl group, a pyradinyl group, a pyrimidinyl group, a pyridazinyl group,
a pyrazolyl group, a quinoxalinyl group, a quinolyl group, a dihydroisoindolyl group, a dihydroindolyl group, a

20 thionaphthenyl group, a naphthyridinyl group, a phenazinyl group, a benzoimidazolyl group, a benzoxazolyl group,

a benzothiazolyl group, a benzotriazolyl group, a benzofuranyl group, a thiazolyl group, a thiadiazolyl group, a
thienyl group, a pyrrolyl group, a furyl group, a furazanyl group, a triazolyl group, a benzodioxanyl group and a
methylenedioxyphenyl group, or an aliphatic heterocyclic group(s) selected from a set of groups consisting of an
isoxazolinyl group, an isoxazolidinyl group, a tetrahydropyridyl group, an imidazolidinyl group, a tetrahydrofuranyl

25 group, a piperazinyl group, a piperidinyl group, a pyrrolidinyl group, pyrrolinyl group, a morpholino group, a tet-

rahydroquinolinyl group and a tetrahydroisoquinolinyl group which may be substituted with one to three of said
substituents; W 20 is a single bond, an oxygen atom, a sulfur atom, SO, S0 2 , NR t0 , SO 2 NR t0 , N(R t0 )SO 2 NR u0 , N
(R t0 )SO 2 , CH(OR t0 ), CONR t0 , N(R t0 )CO, N(R t0 )CONR u0 , N(R t0 )COO, N(R t0 )CSO, N(R t0 )COS, C(R v0 )=CR r0 , C =
C, CO, CS, OC(O), OC(O)NR t0; OC(S)NR t0 , SC(O), SC(O)NR t0 and C(0)0 (wherein: R to and R u0 are each a

30 hydrogen atom or a lower alkyl group, an aryl group or an aralkyl group which may be substituted with one to three

of substituent(s) selected from a set of groups consisting of a lower alkyl group, a hydroxyl group which may be
protected, a cyano group, halogen atoms, a nitro group, a carboxyl group which may be protected, a carbamoyl
group, a formyl group, a lower alkanoyl group, a lower alkanoyloxy group, a hydroxy lower alkyl group which may
be protected, a cyano lower alkyl group, a halo lower alkyl group, a carboxy lower alkyl group which may be

35 protected, a carbamoyl lower alkyl group, lower alkoxy group, a lower alkoxycarbonyl group, lower alkoxycarbo-

nylamino group, a lower alkoxycarbonylamino lower alkyl group, a lower alkylcarbamoyl group, a di-lower alkyl-
carbamoyl group, a carbamoyloxy group, a lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, an
amino group which may be protected, a lower alkylamino group, a di-lower alkylamino group, a tri-lower alkylam-
monio group, an amino lower alkyl group which may be protected, a lower alkylamino lower alkyl group, a di-lower

40 alkylamino lower alkyl group, a tri-lower alkylammonio lower alkyl group, a lower alkanoylamino group, an aroylami-

no group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a
lower alkylsulfonylamino group, a hydroxyimino group which may be protected, and a lower alkoxyimino group, or
said substituent(s)); Y 30 and Y 40 are each, the same or different, a single bond or a straight-chain or branched
lower alkylene group); or a lower alkyl group which may be substituted with one to three of substituent(s) selected

45 from a set of groups consisting of a lower alkyl group, a hydroxyl group which may be protected, a cyano group,

halogen atoms, a nitro group, a carboxyl group which may be protected, a carbamoyl group, a formyl group, a
lower alkanoyl group, a lower alkanoyloxy group, a hydroxy lower alkyl group which may be protected, a cyano
lower alkyl group, a halo lower alkyl group, a carboxy lower alkyl group which may be protected, a carbamoyl lower
alkyl group, lower alkoxy group, a lower alkoxycarbonyl group, lower alkoxycarbonylamino group, a lower alkox-

so ycarbonylamino lower alkyl group, a lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group, a carbamoyloxy

group, a lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, an amino group which may be pro-
tected, a lower alkylamino group, a di-lower alkylamino group, a tri-lower alkylammonio group, an amino lower
alkyl group, a lower alkylamino lower alkyl group, a di-lower alkylamino lower alkyl group, a tri-lower alkylammonio
lower alkyl group, a lower alkanoylamino group, an aroylamino group, a lower alkanoylamidino lower alkyl group,

55 a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a hydroxyimino group

which may be protected, and a lower alkoxyimino group, or a (set of substituents) substituent represented by the
formula Y 30 -W 20 -Y 40 -R s0 (wherein: R s0 , W 20 , Y 30 and Y 40 have the same meanings as stated above), or R 10 forms
a nitrogen atom, together with X; R 20 and R 30 are each independently, the same or different, any of a hydrogen

252

EP 1 199 306 A1

atom, a hydroxy group which may be protected, a lower alkyl group, a lower alkoxy group, or a substituent repre-
sented by the formula Y 30 -W 20 -Y 40 -R s0 (wherein: R s0 , W 20 , Y 30 and Y 40 have the same meanings as stated above),
or either one of R 20 and R 30 forms, together with R 10 and X, a saturated five- to eight-membered cyclic group
selected from a sets of groups consisting of (a) and (b):

and

and the other one binds either to a carbon atom or a nitrogen atom on the ring, or to a carbon atom, an oxygen
atom and/or a nitrogen atom on the ring-substituent(s) on said ring, to form a five- to seven-membered ring, or
R 2 o and R 30 are combined to form a spiro cyclo alkyl group, or to form, together with Z, on which they stand, an
oxo (keto, carbonyl) group, or. to form, together with Z on which they stand, R 10 and X, a heteroaromatic ring
consisting of a saturated or an unsaturated five- to eight-membered cyclic ring selected from sets of groups con-
sisting of (a) and (b)

and

, which may either contain one or more kinds of hetero atoms selected from the group consisting of a nitrogen
atom, an oxygen atom and a sulfur atom, or which may be fused with a ring selected from a cyclo lower alkyl group,
an aryl group, a heteroaromatic ring group selected from a set of groups consisting of an imidazolyl group, an
isoxazolyl group, an isoquinolyl group, an isoindolyl group, an indazolyl group, an indolyl group, an indolydinyl

253

EP 1 199 306 A1

group, an isothiazolyl group, an ethylenedioxyphenyl group, an oxazolyl group, a pyridyl group, a pyradinyl group,
a pyrimidinyl group, a pyridazinyl group, a pyrazolyl group, a quinoxalinyl group, a quinolyl group, a dihydroisoin-
dolyl group, a dihydroindolyl group, a thionaphthenyl group, a naphthyridinyl group, a phenazinyl group, a ben-
zoimidazolyl group, a benzoxazolyl group, a benzothiazolyl group, a benzotriazolyl group, a benzofuranyl group,
a thiazolyl group, a thiadiazolyl group, a thienyl group, a pyrrolyl group, a furyl group, a furazanyl group, a triazolyl
group, a benzodioxanyl group and a methylenedioxyphenyl group, or an aliphatic heterocyclic group(s) selected
from a set of groups consisting of an isoxazolinyl group, an isoxazolidinyl group, a tetrahydropyridyl group, an
imidazolidinyl group, atetrahydrofuranyl group, atetrahydropyranyl group, a piperazinyl group, a piperidinyl group,
a pyrrolidinyl group, pyrrolinyl group, a morpholino group, atetrahydroquinolinyl group and atetrahydroisoquinolinyl
group, which may be substituted with one to three of the same or different substituent(s), selected from a set of
groups consisting of a lower alkyl group, a spiro cyclo lower alkyl group which may be substituted, a hydroxyl group
which may be protected, a cyano group, halogen atoms, a nitro group, a carboxyl group which may be protected,
a carbamoyl group, a formyl group, a lower alkanoyl group, a lower alkanoyloxy group, a hydroxy lower alkyl group
which may be protected, a cyano lower alkyl group, a halo lower alkyl group, a carboxy lower alkyl group which
may be protected, a carbamoyl lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower
alkoxycarbonylamino group, a lower alkoxycarbonylamino lower alkyl group, a lower alkylcarbamoyl group, a di-
lower alkylcarbamoyl group, a carbamoyloxy group, a lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy
group, an amino group which may be protected, a lower alkylamino group, a di-lower alkylamino group, a tri-lower
alkylammonio group, an amino lower alkyl group which may be substituted, a lower alkylamino lower alkyl group,
a di-lower alkylamino lower alkyl group, a tri-lower alkylammonio lower alkyl group, a lower alkanoylamino group,
an aroylamino group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl
group, a lower alkylsulfonylamino group, a hydroxyimino group which may be protected, and a lower alkoxyimino
group, or a set of substituent(s) represented by a formula Y 10 -W 10 -Y 20 -Rpo (wherein: R p0 is a hydrogen atom, or
a lower alkyl group, a lower alkenyl group, or a lower alkynyl group, which may be substituted with one to three of
said substituent(s), or a cyclo lower alkyl group, an aryl group, a hetero aromatic ring group selected from a set of
groups consisting of an imidazolyl group, an isoxazolyl group, an isoquinolyl group, an isoindolyl group, an indazolyl
group, an indolyl group, an indolydinyl group, an isothiazolyl group, an ethylenedioxyphenyl group, an oxazolyl
group, a pyridyl group, a pyradinyl group, a pyrimidinyl group, a pyridazinyl group, a pyrazolyl group, a quinoxalinyl
group, a quinolyl group, a dihydroisoindolyl group, a dihydroindolyl group, a thionaphthenyl group, a naphthyridinyl
group, a phenazinyl group, a benzoimidazolyl group, a benzoxazolyl group, a benzothiazolyl group, a benzotriazolyl
group, a benzofuranyl group, a thiazolyl group, a thiadiazolyl group, a thienyl group, a pyrrolyl group, a furyl group,
a furazanyl group, a triazolyl group, a benzodioxanyl group and a methylenedioxyphenyl group, or an aliphatic
heterocyclic group(s) selected from a set of groups consisting of an isoxazolinyl group, an isoxazolidinyl group, a
tetrahydropyridyl group, an imidazolidinyl group, atetrahydrofuranyl group, atetrahydropyranyl group, a piperazinyl
group, a piperidinyl group, a pyrrolidinyl group, pyrrolinyl group, a morpholino group, a tetrahydroquinolinyl group
and a tetrahydroisoquinolinyl group, which may be substituted with one to three of said substituent(s), or, further-
more, may have on it a bicyclic or tricyclic fused ring which contains a partial structure selected from a set of groups
comprising:

; W 10 is a single bond, an oxygen atom, a sulfur atom, SO, S0 2 , NR q0 , SO 2 NR q0 , N(R q0 )SO 2 NR r0 , N(R q0 )SO 2 ,
CH(OR q0 ), CONR q0 , N(R q0 )CO, N(R q0 )CONR q0 , N(R q0 )COO, N(R q0 )CSO, N(R q0 )COS, C(R q0 )=CR r0 , C=C, CO,
CS, OC(O), OC(O)NR q0 , OC(S)NR q0 , SC(O), SC(O)NR q0 and C(0)0 (wherein: R q0 and R r0 are each either a
hydrogen atom or a lower alkyl group, an aryl group or an aralkyl group which may be substituted with one to three
of substitutent(s) selected from a set of groups consisting of a lower alkyl group, a cyclo lower alkyl group, a
hydroxyl group which may be protected, a cyano group, halogen atoms, a nitro group : a carboxyl group which may
be protected, a carbamoyl group, a formyl group, a lower alkanoyl group, a lower alkanoyloxy group, a hydroxy
lower alkyl group which may be protected, a cyano lower alkyl group, a halo lower alkyl group, a carboxy lower
alkyl group which may be protected, a carbamoyl lower alkyl group, lower alkoxy group, a lower alkoxycarbonyl
group, lower alkoxycarbonylamino group, a lower alkoxycarbonylamino lower alkyl group, a lower alkylcarbamoyl
group, a di-lower alkylcarbamoyl group, a carbamoyloxy group, a lower alkylcarbamoyloxy group, di-lower alkyl-
carbamoyloxy group, an amino group which may be protected, a lower alkylamino group, a di-lower alkylamino
group, a tri-lower alkylammonio group, an amino lower alkyl group which may be protected, a lower alkylamino

and

254

EP 1 199 306 A1

lower alkyl group, a di-lower alkylamino lower alkyl group, a tri-lower alkylammonio lower alkyl group, a lower
alkanoylamino group, an aroylamino group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group,
a lower alkylsulfonyl group, a lower alkylsulfonylamirio group, a hydroxyimino group which may be protected, and
a lower alkoxyimino group, or from said substituent(s)); Y 10 and Y 20 are each, the same or different, a single bond
or a straight-chain or branched lower alkylene group which may have a bicyclic or tricyclic fused ring); R 40 and
R 50 are each, the same or different, either a hydrogen atom, halogen atoms, a hydroxyl which may be protected,
an amino group which may be protected, or a lower alkyl group, an aryl group or an aralkyl group which may be
substituted with one to three of the same or different substituents selected from a set of the groups consisting of:
the one represented by the formula Y 30 -W 20 -Y 40 -R s0 (wherein: R s0 , W 20 , Y 30 and Y 40 have the same meanings
as stated above), the one which may be selected from a set of groups consisting of a lower alkyl group, a cyano
group, a nitro group, a carboxyl group which may be protected, a carbamoyl group, aformyl group, a lower alkanoyl
group, a lower alkanoyloxy group, a hydroxy lower alkyl group which may be protected, a cyano lower alkyl group,
a halo lower alkyl group, a carboxy lower alkyl group which may be protected, a carbamoyl lower alkyl group, a
lower alkoxy group, a lower alkoxycarbonyl group, lower alkoxycarbonylamino group, a lower alkoxycarbonylamino
lower alkyl group, a lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group, a carbamoyloxy group, a lower
alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, an amino group which may be protected, a lower
alkylamino group, a di-lower alkylamino group, a tri-lower alkylammonio group, an amino lower alkyl group which
may be protected, a lower alkylamino lower alkyl group, a di-lower alkylamino lower alkyl group, a tri-lower alky-
lammonio lower alkyl group, a lower alkanoylamino group, an aroylamino group, a lower alkanoylamidino lower
alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a hydroxy-
imino group which may be protected, and a lower alkoxyimino group, and the one represented by the formula Y 30 -
W2o-Y 40 -R s o (wherein: R s0 , W 20 , Y 30 and Y 40 have the same meanings as stated above); the Formula ~ is a single
bond or a double bond, or

is made to react with a compound represented by Formula (IV)

Formula (IV)
N 3 Ar 0

wherein: Ar 0 is a nitrogen-containing heteroaromatic ring group selected from a set of groups consisting of a pyridyl
group, a pyrimidinyl group, a pyradinyl group, a pyridazinyl group ; a thiazolyl group ; an isothiazolyl group, an
oxazolyl group, an isoxazolyl group, a pyrazolyl group, a pyrrolyl group, an imidazolyl group, an indolyl group, an
isoindolyl group, a quinolyl group, an isoquinolyl group, a benzothiazolyl group, a benzoxazolyl group, which:

1) may be substituted with one to three of the same or different substituent(s) selected from a set of groups
a lower alkyl group, a hydroxyl group which may be protected, a cyano group, halogen atoms, a nitro group,
a carboxyl group which may be protected, a carbamoyl group, aformyl group, a lower alkanoyl group, a lower
alkanoyloxy group, a hydroxy lower alkyl group which may be protected, a cyano lower alkyl group, a halo
lower alkyl group, a carboxy lower alkyl group which may be protected, a carbamoyl lower alkyl group, lower
alkoxy group, a lower alkoxycarbonyl group, lower alkoxycarbonylamino group, a lower alkoxycarbonylamino
lower alkyl group, a lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group, a carbamoyloxy group, a
lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, an amino group which may be protected,
a lower alkylamino group, a di-lower alkylamino group, a tri-lower alkylammonio group, an amino lower alkyl
group, a lower alkylamino lower alkyl group, a di-lower alkylamino lower alkyl group, a tri-lower alkylammonio
lower alkyl group, a lower alkanoylamino group, an aroylamino group, a lower alkanoylamidino lower alkyl
group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a hydroxyimino
group which may be protected and a lower alkoxyimino group, or a substituent selected from groups repre-
sented by a formula Y 10 -W 10 -Y 20 -R p0 (wherein: R p0 , W 10 , Y 10 and Y 2 o have the same meanings as stated
above); or

2) may have a five- to seven-membered ring selected from a set of groups consisting of

255

EP 1 199 306 A1

, which may be protected, and together with the carbon atom on the ring on which the substituent selected
from a set of groups consisting of a lower alkyl group, a lower alkanoyl group, a lower alkanoyloxy group, a
hydroxy lower alkyl group which may be protected, a cyano lower alkyl group, a halo lower alkyl group, a
carboxy lower alkyl group which may be protected, a carbamoyl lower alkyl group, a lower alkoxy group, a
lower alkoxycarbonyl group, a lower alkoxycarbonylamino group, a lower alkoxycarbonylamino lower alkyl
group, a lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group, a carbamoyloxy group, a lower alkyl-
carbamoyloxy group, a di-lower a Iky I carbamoyloxy group, a lower alkylamino group, a di-lower alkylamino
group, atri-loweralkylammonio group, an amino lower alkyl group which may be protected, a lower alkylamino
lower alkyl group, a di-lower alkylamino lower alkyl group, a tri-lower alkylammonio lower alkyl group, a lower
alkanoylamino group, an aroylamino group, a lower alkylfulfinyl group, a lower alkylsulfonyl group, a lower
alkylsulfonylamino group and a lower alkanoylamidino lower alkyl group (hereinafter indecated as ring-sub-
stituent(s) which may be protected) stands, a carbon atom next to said carbon atom and a carbon atom, an
oxygen atom and/or a nitrogen atom on said ring-substituent(s) which may be protected, all taken together; or
3) may have a five- to seven-membered ring selected from a set of groups consisting of

, which may be protected, and together with the carbon atom on the ring on which a substituent selected from
groups represented by the formula of Y 10 -W 10 -Y 2 o-Rpo (wherein: Y 10 ,W 10 ,Y 2 o and R p0 have the same mean-
ings as stated above) stands, a carbon atom next to said carbon atom and a carbon atom, an oxygen atom
and/or a nitrogen atom on said ring-substituent(s) which may be protected, all taken together, to give a com-
pound of Formula (II)

Formula (II)

R

30 H

HN ^Sw <»>

J \ °

"40 Rso

256

EP 1 199 306 A1

, wherein Ar 0 , X, Y, Z, R-| 0 , R 2 o, R40 an d tne Formula ™ have the same meanings as stated above, and
then, if necessary, removing the protecting group(s), to give a compound of Formula (I) according to claim 1
and pharmaceutical^ acceptable salts thereof:

, wherein: Ar is a nitrogen-containing heteroaromatic ring group selected from the groups consisting of a pyridyl
group, a pyrimidinyl group, a pyradinyl group, a pyridazinyl group, athiazolyl group, an isothiazolyl group, an
oxazolyl group, an isoxazolyl group, a pyrazolyl group, a pyrrolyl group, an imidazolyl group, an indolyl group,
an isoindolyl group, a quinolyl group, an isoquinolyl group, a benzothiazolyl group, and a benzoxazolyl group,
and said nitrogen-containing heteroaromatic ring group, which:

1 ) may be optionaly substituted with one to three of the same or different substituent(s) selected from a set of
groups consisting of a lower alkyl group, a hydroxyl group, a cyano group, halogen atoms, a nitro group, a
carboxyl group, a carbamoyl group, a formyl group, a lower alkanoyl group, a lower alkanoyloxy group, a
hydroxy lower alkyl group, a cyano lower alkyl group, a halo lower alkyl group, a carboxy lower alkyl group, a
carbamoyl lower alkyl group, lower alkoxy group, a lower alkoxycarbonyl group, lower alkoxycarbonylamino
group, a lower alkoxycarbonylamino lower alkyl group, a loweralkylcarbamoyl group, a di-loweralkylcarbamoyl
group, a carbamoyloxy group, a lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, an amino
group, a lower alkylamino group, a di-lower alkylamino group, a tri-lower alkylammonio group, an amino lower
alkyl group, a lower alkylamino lower alkyl group, a di-lower alkylamino lower alkyl group, a tri-lower alkylam-
monio lower alkyl group, a lower alkanoylamino group, an aroylamino group, a lower alkanoylamidino lower
alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a hy-
droxyimino group and a lower alkoxyimino group, or groups represented by a formula Y 1 -W 1 -Y 2 -R p (wherein:
R p is any of a hydrogen atom, or a lower alkyl group, a lower alkenyl group or a lower alkynyl group which
may be substituted with one to three of said substituents, or a cyclo lower alkyl group ; an aryl group, or a
heteroaromatic ring group selected from a set of groups consisting of an imidazolyl group, an isoxazolyl group,
an isoquinolyl group, an isoindolyl group, an indazolyl group, an indolyl group, an indolizinyl group, an isothi-
azolyl group, an ethylenedioxyphenyl group, an oxazolyl group, a pyridyl group, a pyradinyl group, a pyrimidinyl
group, a pyridazinyl group, a pyrazolyl group, a quinoxalinyl group, a quinolyl group, a dihydroisoindolyl group,
a dihydroindolyl group, athionaphthenyl group, a naphthyridinyl group, a phenazinyl group, a benzoimidazolyl
group, a benzoxazolyl group, a benzothiazolyl group, a benzotriazolyl group, a benzofuranyl group, a thiazolyl
group, a thiadiazolyl group, a thienyl group, a pyrrolyl group, afuryl group, afurazanyl group, atriazolyl group,
a benzodioxanyl group and a methylenedioxyphenyl group, or an aliphatic heterocyclic group(s) selected from
a set of groups consisting of an isoxazolinyl group, an isoxazolidinyl group, a tetrahydropyridyl group, an
imidazolidinyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a piperazinyl group, a piperidinyl
group, a pyrrolidinyl group, pyrrolinyl group, a morpholino group, a tetrahydroquinolinyl group and a tetrahy-
droisoquinolinyl group, each of which(heteroaromatic ring groups and aliphatic heterocyclic groups) may be
substituted with one to three of the same or different said substituent(s), which are same or different, or fur-
thermore, may have (on it) a bicyclic or tricyclic fused ring of a partial structure selected from a set of groups
consisting of:

and

; W 1 is a single bond, an oxygen atom, a sulfur atom, SO, S0 2 , NR q , S0 2 NR q , N(R q )S0 2 NR r , N(R q )S0 2 , CH

257

EP 1 199 306 A1

(O), OC(0)NR q , OC(S)NR q , SC(O), SC(0)NR q and C(0)0 (wherein: R q and R r are each, a hydrogen atom
or a lower alkyl group, an aryl group or an aralkyl group, which may be substituted with one to three substituent
(s) selected from a set of groups consisting of a lower alkyl group, a cyclo lower alkyl group, a hydroxyl group,
a cyano group, halogen atoms, a nitro group, a carboxyl group, a carbamoyl group, a formyl group, a lower
alkanoyl group, a lower alkanoyloxy group, a hydroxy lower alkyl group, a cyano lower alkyl group, a halo
lower alkyl group, a carboxy lower alkyl group, a carbamoyl lower alkyl group, lower alkoxy group, a lower
alkoxycarbonyl group, lower alkoxycarbonylamino group, a lower alkoxycarbonylamino lower alkyl group, a
lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group, a carbamoyloxy group, a lower alkylcarbamoy-
loxy group, di-lower alkylcarbamoyloxy group, an amino group, a lower alkylamino group, a di-lower alkylamino
group, a tri-lower alkylammonio group, an amino lower alkyl group, a lower alkylamino lower alkyl group, a di-
lower alkylamino lower alkyl group, a tri-lower alkylammonio lower alkyl group, a lower alkanoylamino group,
an aroylamino group, a lower alkanoylamidino lower alkyl group, a lower alkylsulf inyl group, a lower alkylsul-
fonyl group, a lower alkylsulfonylamino group, a hydroxyimino group and a lower alkoxyimino group, or a lower
alkyl group, an aryl group or an aralkyl group which may be substituted with one to three of said substituent
(s).): Yi and Y 2 are each, the same or different, a single bond or a straight-chain or branched lower alkylene
group which may have a said bicyclic or tricyclic fused ring);

2) may have a five- to seven-membered fused ring selected from a set of groups consisting of:

which may be together with the carbon atom of said nitrogen-containing heteroaromatic cyclic group, on which
the substituent, which is selected from a set of groups consisting of consisting of a lower alkyl group, a lower
alkanoyl group, a lower alkanoyloxy group, a hydroxy lower alkyl group, a cyano lower alkyl group, a halo
lower alkyl group, a carboxy lower alkyl group, a carbamoyl lower alkyl group, lower alkoxy group, a lower
alkoxycarbonyl group, lower alkoxycarbonylamino group, a lower alkoxycarbonylamino lower alkyl group, a
lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group, a carbamoyloxy group, a lower alkylcarbamoy-
loxy group, di-lower alkylcarbamoyloxy group, a lower alkylamino group, a di-lower alkylamino group, a tri-
lower alkylammonio group, an amino lower alkyl group, a lower alkylamino lower alkyl group, a di-lower
alkylamino lower alkyl group, a tri-lower alkylammonio lower alkyl group, a lower alkanoylamino group, an
aroylamino group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group,
and a lower alkanoylamidino lower alkyl group (hereinafter indicated as ring-substituent) stands, the carbon
atom next to said carbon atom, and a carbon atom, an oxygen atom and/or a nitrogen atom on said ring-
substituent;
or,

3) may form a five- to seven-membered ring selected from a set of groups consisting of:

and

9

and

258

EP 1 199 306 A1

which may be formed from the carbon atom on which a substituent represented by the formula Y-|-W.|-Y 2 -R p
(wherein: Y-|, W-|, Y 2 and R p have the same meanings as stated above) stands, the carbon atom next to said
carbon atom, and a carbon atom, an oxygen atom and/or a nitrogen atom on said ring-substituent; X and Z
are each, the same or different, a carbon atom or a nitrogen atom, or being taken together with R 1 or R 2 and/

5 or R 3 which may exist on X and Z, forms a CH or a nitrogen atom; Y is CO, SO or S0 2 ;

R 1 is any of a hydrogen atom or a substituent represented by a formula Y 3 -W 2 -Y 4 -R s (wherein: R s is any of a
hydrogen atom or a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cyclo lower alkyl group,
an aryl group, and a heteroaromatic ring group which is selected from a set of groups consisting of an imidazolyl
group, an isoxazolyl group, an isoquinolyl group, an isoindolyl group, an indazolyl group, an indolyl group, an

10 indolizinyl group, an isothiazolyl group, an ethylenedioxyphenyl group, an oxazolyl group, a pyridyl group, a

pyradinyl group, a pyrimidinyl group, a pyridazinyl group, a pyrazolyl group, a quinoxalinyl group, a quinolyl
group, a dihydroisoindolyl group, a dihydroindolyl group, a thionaphthenyl group, a naphthyridinyl group, a
phenazinyl group, a benzoimidazolyl group, a benzoxazolyl group, a benzothiazolyl group, a benzotriazolyl
group, a benzofuranyl group, a thiazolyl group, a thiadiazolyl group, a thienyl group, a pyrrolyl group, a furyl

15 group, a furazanyl group, a triazolyl group, a benzodioxanyl group and a methylenedioxyphenyl group, or an

aliphatic heterocyclic group selected from a set of groups consisting of an isoxazolinyl group, an isoxazolidinyl
group, a tetrahydropyridyl group, an imidazolidinyl group, a tetrahydrofuranyl group, a piperazinyl group, a
piperidinyl group, a pyrrolidinyl group, pyrrolinyl group, a morpholino group, a tetrahydroquinolinyl group and
a tetrahydroisoquinolinyl group, all of which may be substituted with one to three of said substituent(s); W 2 is

20 a single bond, an oxygen atom, a sulfur atom, SO, S0 2 , NR t , S0 2 NR t , N(R t )S0 2 NR u , N(R t )S0 2 , CH(OR t ),

CONR t , N(R t )CO, N(R t )CONR u , N(R t )COO, N(R t )CSO, N(R t )COS, C(R v )=CR r , C=C, CO, CS, OC(O), OC(O)
NR t , OC(S)NR t , SC(O), SC(0)NR t and C(0)0 (wherein: R t and R u are each a hydrogen atom or a substituent
selected from a set of groups consisting of a lower alkyl group, a hydroxyl group, a cyano group, halogen
atoms, a nitro group, a carboxyl group, a carbamoyl group, a formyl group, a lower alkanoyl group, a lower

25 alkanoyloxy group, a hydroxy lower alkyl group, a cyano lower alkyl group, a halo lower alkyl group, a carboxy

lower alkyl group, a carbamoyl lower alkyl group, lower alkoxy group, a lower alkoxycarbonyl group, lower
alkoxycarbonylamino group, a lower alkoxycarbonylamino lower alkyl group, a lower alkylcarbamoyl group, a
di-lower alkylcarbamoyl group, a carbamoyloxy group, a lower alkylcarbamoyloxy group, di-lower alkylcar-
bamoyloxy group, an amino group, a lower alkylamino group, a di-lower alkylamino group, a tri-lower alkylam-

30 monio group, an amino lower alkyl group, a lower alkylamino lower alkyl group, a di-lower alkylamino lower

alkyl group, a tri-lower alkylammonio lower alkyl group, a lower alkanoylamino group, an aroylamino group, a
lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkyl-
sulfonylamino group, a hydroxyimino group and a lower alkoxyimino group, or a lower alkyl group, an aryl
group or an aralkyl group which may be substituted with one to three of said substituent(s)); Y 3 and Y 4 are

35 each, the same or different, a single bond or a straight-chain or branched lower alkylene group), or R-| is a

lower alkyl group which may be substituted with one to three of the same or different substituent(s) which is
selected from a set of groups consisting of a lower alkyl group, a hydroxyl group, a cyano group, halogen
atoms, a nitro group, a carboxyl group, a carbamoyl group, a formyl group, a lower alkanoyl group, a lower
alkanoyloxy group, a hydroxy lower alkyl group, a cyano lower alkyl group, a halo lower alkyl group, a carboxy

40 lower alkyl group, a carbamoyl lower alkyl group, lower alkoxy group, a lower alkoxycarbonyl group, lower

alkoxycarbonylamino group, a lower alkoxycarbonylamino lower alkyl group, a lower alkylcarbamoyl group, a
di-lower alkylcarbamoyl group, a carbamoyloxy group, a lower alkylcarbamoyloxy group, di-lower alkylcar-
bamoyloxy group, an amino group, a lower alkylamino group, a di-lower alkylamino group, a tri-lower alkylam-
monio group, an amino lower alkyl group, a lower alkylamino lower alkyl group, a di-lower alkylamino lower

45 alkyl group, a tri-lower alkylammonio lower alkyl group, a lower alkanoylamino group, an aroylamino group, a

lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkyl-
sulfonylamino group, a hydroxyimino group and a lower alkoxyimino group, or a substituent or substituents
selected from groups represented by the formula Y 3 -W 2 -Y 4 -R s (wherein: R s , W 2 , Y 3 and Y 4 have the same
meanings as stated above), or R 1 forms a nitrogen atom together with X.); R 2 and R 3 are each independently,

50 the same or different, a hydrogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, or a

substituent represented by the formula Y 3 -W 2 -Y 4 -R s ( wherein: R s , W 2 , Y 3 and Y 4 have the same meanings
as stated above), or either one of R 2 or R 3 forms, together with R 1 andX, a saturated five- to eight-membered
cyclic group selected from sets of groups of (a) and (b):

55

259

EP 1 199 306 A1

and

and the another one of R 2 or R 3 binds to a carbon atom or a nitrogen atom on the ring, or to a carbon atom,
an oxygen atom and/or nitrogen atom on said ring-substituent to form a five- to seven-membered ring, or R 2
and R 3 are combined to form a spiro cyclo lower alkyl group, or are together furthermore with Z to which they
bind to form an oxo (keto, or carbonyl) group, or they (R 2 and R 3 ) form, together with Z, R 1 and X, on which
they stand, a saturated or an unsaturated five- to eight membered cyclic group which may be selected from
sets of groups of (a) and (b):

, which may contain one or more kinds of hetero atom(s) selected from a group of a nitrogen atom, an oxygen
atom and a sulfur atom, or which may be fused with any of a cyclo lower alkyl group, an aryl group, a heter-
oaromatic ring group selected from a set of groups consisting of an imidazolyl group, an isoxazolyl group, an
isoquinolyl group, an isoindolyl group, an indazolyl group, an indolyl group, an indolydinyl group, an isothiazolyl
group, an ethylenedioxyphenyl group, an oxazolyl group, a pyridyl group, a pyradinyl group, a pyrimidinyl
group, a pyridazinyl group, a pyrazolyl group, a quinoxalinyl group, a quinolyl group, a dihydroisoindolyl group,
a dihydroindolyl group, athionaphthenyl group, a naphthyridinyl group, a phenazinyl group, a benzoimidazolyl
group, a benzoxazolyl group, a benzothiazolyl group, a benzotriazolyl group, a benzofuranyl group, a thiazolyl
group, a thiadiazolyl group, a thienyl group, a pyrrolyl group, afuryl group, a furazanyl group, a triazolyl group,
a benzodioxanyl group and a methylenedioxyphenyl group, or an aliphatic heterocyclic group(s) selected from
a set of groups consisting of an isoxazolinyl group, an isoxazolidinyl group, a tetrahydropyridyl group, an
imidazolidinyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a piperazinyl group, a piperidinyl

260

EP 1 199 306 A1

group, a pyrrolidinyl group, pyrrolinyl group, a morpholino group, a tetrahydroquinolinyl group and a tetrahy-
droisoquinolinyl group, which may be substituted with one to three of the same or different substituent(s)
selected from a set of groups consisting of a lower alkyl group, a spiro cyclo lower alkyl group which may be
substituted, a hydroxyl group, a cyano group, halogen atoms, a nitro group, a carboxyl group, a carbamoyl
group, aformyl group, a lower alkanoyl group, a lower alkanoyloxy group, a hydroxy lower alkyl group, a cyano
lower alkyl group, a halo lower alkyl group, a carboxy lower alkyl group, a carbamoyl lower alkyl group, lower
alkoxy group, a lower alkoxycarbonyl group, lower alkoxycarbonylamino group, a lower alkoxycarbonylamino
lower alkyl group, a lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group, a carbamoyloxy group, a
lower alkyl carbamoyloxy group, di-lower alkylcarbamoyloxy group, an amino group, a lower alkylamino group,
a di-lower alkylamino group, a tri-lower alkylammonio group, an amino lower alkyl group, a lower alkylamino
lower alkyl group, a di-lower alkylamino lower alkyl group, a tri-lower alkylammonio lower alkyl group, a lower
alkanoylamino group, an aroylamino group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl
group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a hydroxyimino group and a lower alkox-
yimino group, and a substituent or substituents selected from groups represented by the formula Y 1 -W 1 -Y 2 -
R p (wherein: R p , W-|, Yi and Y 2 have the same meanings as stated above); R 4 and R 5 are each, the same or
different, a hydrogen atom, halogen atoms, a hydroxy group, an amino group, or a substituent represented
by the formula Y 3 -W 2 -Y 4 -R s (wherein: R s , W 2 , Y 3 and Y 4 have the same meanings as stated above), or any
of a lower alkyl group, an aryl group or an aralkyl group which may be substituted with one to three of the
same or different substituent(s) selected from both a set of groups consisting of a lower alkyl group, a cyano
group, a nitro group, a carboxyl group, a carbamoyl group, a formyl group, a lower alkanoyl group, a lower
alkanoyloxy group, a hydroxy lower alkyl group, a cyano lower alkyl group, a halo lower alkyl group, a carboxy
lower alkyl group, a carbamoyl lower alkyl group, lower alkoxy group, a lower alkoxycarbonyl group, lower
alkoxycarbonylamino group, a lower alkoxycarbonylamino lower alkyl group, a lower alkylcarbamoyl group, a
di-lower alkylcarbamoyl group, a carbamoyloxy group, a lower alkylcarbamoyloxy group, di-lower alkylcar-
bamoyloxy group, an amino group, a lower alkylamino group, a di-lower alkylamino group, a tri-lower alkylam-
monio group, an amino lower alkyl group, a lower alkylamino lower alkyl group, a di-lower alkylamino lower
alkyl group, a tri-lower alkylammonio lower alkyl group, a lower alkanoylamino group, an aroylamino group, a
lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkyl-
sulfonylamino group, a hydroxyimino group and a lower alkoxyimino group, and groups represented by the
formula Y 3 -W 2 -Y 4 -R s (wherein: R s , W 2 , Y 3 and Y 4 have the same meanings as stated above); and the formula
™ represents either a single bond or a double bond.

A method of preparing a compound of Formula (I) or pharmaceutically acceptable salts thereof:

Formula ( I )

R 4

, wherein: Ar, X, Y, Z, R 1; R 2 , R 3 , R 4 , R 5 and the formula™ have the same meanings as stated above
characterized by reacting a compound represented by Formula (V):

Formula (V)

f\o R

261

EP 1 199 306 A1

, wherein: X, Y, Z, R-| 0 , R 20 , R30, R40. R50 ar| d the formula ™ have the same meanings as stated above,
with a compound represented with Formula (VI):
Formula (VI)

H 2 N-Ar 0 (VI)
, wherein: Ar 0 have the same meanings as stated above, to give a compound of Formula (II):

Formula (II)
^0 ^20

R40 R50

, wherein: Ar 0 , X, Y, Z, R 10 , R 20 , R3o> FUo> ^50 ar| d tne formula — have the same meanings as stated above
, and then, by removing, if necessary, the protective group(s).

A method for preparing a compound of Formula (I")

Formula ( I ' ' )

, wherein: T-| is any of a single bond or a straight-chain or branched lower alkylene, an aryl group, a heteroromatic
ring group, an aliphatic heterocyclic group, and an Ar which has a convertible functional group(s)including or an
aralkyl group; Q is W-|-Y2-Rp (wherein: W-|, Y 2 and R p have the same meanings as stated above), X, Y, Z, R-,, R 2 ,
R 3 , R 4 , R 5 and the formula --- have the same meanings as stated above, and salts thereof characterized by first
making a compound of a formula (VII):

Formula (VII)
O

, wherein: L is a reactive substituent which may be protected, and may have a functional group which can be
converted into other functional group, T 10 is any of a single bond or , if appropriate, a straight-chain or branched
lower alkylene group which may have a protected substituent(s), an aryl group, a heteroaromatic ring group, an
aliphatic heterocyclic group, and an Ar 0 which has a convertiblefunctional group including an aralkyl group, reacting
with a compound of a formula (VIII):
Formula (VIII)

262

EP 1 199 306 A1

H 2 N-NH-R 60 (VIII)
wherein: R 60 is a hydrogen atom or a protective group for an amino group, to obtain a compound of a formula (IX):

Formula (IX)

(IX)

, wherein: Ti 0 , ar| d L have the same meanings as stated above,

and then by making said compound react with a compound of a Formula (III):

Formula (III)

(III)

, wherein: X, Y, Z, R 10 , R 20 , F! 30 , Fi 40; R50 ar| d tne formula ™ have the same meanings as stated above] and one
of reactive derivatives of formate ester, if necessary, in the presence of a base ro give a compound of a formula (X):

Formula (X)

(X)

'40 R50 T 10

l'

, wherein: X, Y, Z, T 10 , Rio> ^20* ^30> FUo> ^50* ^60 anc ' tne formula = have the same meanings as stated above,
and by subjecting the compound obtained to transformation reaction of the substituent L and/or removal of the
protective group.

A Cdk4 and/or Cdk6 inhibitory drug containing as the active ingredient a compound of Formula (I) and pharma-
ceutical^ acceptable salts thereof:

263

EP 1 199 306 A1

Formula ( I )

, wherein: Ar is a nitrogen-containing hetero aromatic ring group selected from a set of groups consisting of a pyridyl
group, a pyrimidinyl group, a pyradinyl group, a pyridazinyl group, a thiazolyl group, an isothiazolyl group, an
oxazolyl group, an isoxazolyl group, a pyrazolyl group, a pyrrolyl group, an imidazolyl group, an indolyl group, an
isoindolyl group, a quinolyl group, an isoquinolyl group, a benzothiazolyl group, and a benzoxazolyl group, which:

1) may be substituted with one to three of the same or different substituent(s) selected from a set of groups
consisting of a lower alkyl group, a hydroxyl group, a cyano group, halogen atoms, a nitro group, a carboxyl
group, a carbamoyl group, a formyl group, a lower alkanoyl group, a lower alkanoyloxy group, a hydroxy lower
alkyl group, a cyano lower alkyl group, a halo lower alkyl group, a carboxy lower alkyl group, a carbamoyl
lower alkyl group, lower alkoxy group, a lower alkoxycarbonyl group, lower alkoxycarbonylamino group, a
lower alkoxycarbonylamino lower alkyl group, a lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group,
a carbamoyloxy group, a lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, an amino group,
a lower alkylamino group, a di-lower alkylamino group, a tri-lower alkylammonio group, an amino lower alkyl
group, a lower alkylamino lower alkyl group, a di-lower alkylamino lower alkyl group, a tri-lower alkylammonio
lower alkyl group, a lower alkanoylamino group, an aroylamino group, a lower alkanoylamidino lower alkyl
group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a hydroxyimino
group and a lower alkoxyimino group, and groups represented by a formula Y 1 -W 1 -Y 2 -R p (wherein: R p is any
of a hydrogen atom, or a lower alkyl group, a lower alkenyl group or a lower alkynyl group which may be
substituted with one to three of said substituents, or a cyclo lower alkyl group, an aryl group, a hetero aromatic
ring group selected from a set of groups consisting of an imidazolyl group, an isoxazolyl group, an isoquinolyl
group, an isoindolyl group, an indazolyl group, an indolyl group, an indolizinyl group, an isothiazolyl group, an
ethylenedioxyphenyl group, an oxazolyl group, a pyridyl group, a pyradinyl group, a pyrimidinyl group, a pyri-
dazinyl group, a pyrazolyl group, a quinoxalinyl group, a quinolyl group, a dihydroisoindolyl group, a dihydroin-
dolyl group, a thionaphthenyl group, a naphthyridinyl group, a phenazinyl group, a benzoimidazolyl group, a
benzoxazolyl group, a benzothiazolyl group, a benzotriazolyl group, a benzofuranyl group, a thiazolyl group,
a thiadiazolyl group, a thienyl group, a pyrrolyl group, a furyl group, a furazanyl group, a triazolyl group, a
benzodioxanyl group and a methylenedioxyphenyl group, or an aliphatic heterocyclic group(s) selected from
a set of groups consisting of an isoxazolinyl group, an isoxazolidinyl group, a tetrahydropyridyl group, an
imidazolidinyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a piperazinyl group, a piperidinyl
group, a pyrrolidinyl group, pyrrolinyl group, a morpholino group, a tetrahydroquinolinyl group and a tetrahy-
droisoquinolinyl group, each of which cyclic group may be substituted with one to three of said substituents
or, furthermore, may have (on it) a bicyclic or tricyclic fused ring of a partial structure selected from a set of
groups consisting of:

; W 1 is a single bond, an oxygen atom, a sulfur atom, SO, S0 2 , NR q , S0 2 NR q! N(R q )S0 2 NR r , N(R q )S0 2 , CH
(OR q ), CONR q , N(R q )CO, N(R q )CONR r , N(R q )COO, N(R q )CSO, N(R q )COS, C(R q )=CR r , C=C, CO, CS, OC
(O), OC(0)NR q , OC(S)NR q , SC(O), SC(0)NR q and C(0)0 (wherein: R q and R r are each a hydrogen atom or
a lower alkyl group, an aryl group or an aralkyl group, which may be substituted with one to three substituent
(s) selected from a set of groups consisting of a lower alkyl group, a cyclo lower alkyl group, a hydroxyl group,
a cyano group, halogen atoms, a nitro group, a carboxyl group, a carbamoyl group, a formyl group, a lower
alkanoyl group, a lower alkanoyloxy group, a hydroxy lower alkyl group, a cyano lower alkyl group, a halo
lower alkyl group, a carboxy lower alkyl group, a carbamoyl lower alkyl group, lower alkoxy group, a lower

and

264

EP 1 199 306 A1

alkoxycarbonyl group, lower alkoxycarbonylamino group, a lower alkoxycarbonylamino lower alkyl group, a
lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group, a carbamoyloxy group, a lower alkylcarbamoy-
loxy group, di-lower alkylcarbamoyloxy group, an amino group, a lower alkylamino group, a di-lower alkylamino
group, a tri-lower alkylammonio group, an amino lower alkyl group, a lower alkylamino lower alkyl group, a di-
lower alkylamino lower alkyl group, a tri-lower alkylammonio lower alkyl group, a lower alkanoylamino group,
an aroylamino group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsul-
fonyl group, a lower alkylsulfonylamino group, a hydroxyimino group and a lower alkoxyimino group, and which
may have one to three said substituent or substituents.); Y 1 and Y 2 are each, the same or different, a single
bond ora straight-chain or branched lower alkylene group which may have a said bicyclic ortricyclicfused ring);
2) may have a five- to seven-membered fused ring selected from a set of groups consisting of:

which may be together with the carbon atom of said nitrogen-containing heteroaromatic ring group, on which
the substituent, which is selected from a set of groups consisting of consisting of a lower alkyl group, a lower
alkanoyl group, a lower alkanoyloxy group, a hydroxy lower alkyl group, a cyano lower alkyl group, a halo
lower alkyl group, a carboxy lower alkyl group, a carbamoyl lower alkyl group, lower alkoxy group, a lower
alkoxycarbonyl group, lower alkoxycarbonylamino group, a lower alkoxycarbonylamino lower alkyl group, a
lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group, a carbamoyloxy group, a lower alkylcarbamoy-
loxy group, di-lower alkylcarbamoyloxy group, a lower alkylamino group, a di-lower alkylamino group, a tri-
lower alkylammonio group, an amino lower alkyl group, a lower alkylamino lower alkyl group, a di-lower
alkylamino lower alkyl group, a tri-lower alkylammonio lower alkyl group, a lower alkanoylamino group, an
aroylamino group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group,
and a lower alkanoylamidino lower alkyl group (hereinafter indicated as ring-substituent) stands, the carbon
atom next to said carbon atom, and a carbon atom, an oxygen atom and/or a nitrogen atom on said ring-
substituent;
or,

3) may form a five- to seven-membered ring selected from a set of groups consisting of:

which may formed from the carbon atom on which a substituent represented by the formula Y 1 -W 1 -Y 2 -R p
(wherein: Y 2 and R p have the same meanings as stated above) stands, the carbon atom next to said

carbon atom, and a carbon atom, an oxygen atom and/or a nitrogen atom on said ring-substituent.
; X and Z are each, the same or different, a carbon atom or a nitrogen atom, or being taken together with R-|
or R 2 and/or R 3 which may exist on X or Z, forms a CH or a nitrogen atom; Y is CO, SO or S0 2 ; R 1 is any of
a hydrogen atom or a substituent represented by a formula Y 3 -W 2 -Y 4 -R s (wherein: R s is a hydrogen atom or

265

EP 1 199 306 A1

a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cyclo lower alkyl group, an aryl group, and
a heteroaromatic ring group selected from a set of groups consisting of an imidazolyl group, an isoxazolyl
group, an isoquinolyl group, an isoindolyl group, an indazolyl group, an indolyl group, an indolizinyl group, an
isothiazolyl group, an ethylenedioxyphenyl group, an oxazolyl group, a pyridyl group, a pyradinyl group, a
pyrimidinyl group, a pyridazinyl group, a pyrazolyl group, a quinoxalinyl group, a quinolyl group, a dihydroi-
soindolyl group, a dihydroindolyl group, a thionaphthenyl group, a naphthyridinyl group, a phenazinyl group,
a benzoimidazolyl group, a benzoxazolyl group, a benzothiazolyl group, a benzotriazolyl group, a benzof uranyl
group, athiazolyl group, athiadiazolyl group, athienyl group, a pyrrolyl group, afuryl group, afurazanyl group,
a triazolyl group, a benzodioxanyl group and a methylenedioxyphenyl group, or an aliphatic heterocyclic group
(which is) selected from a set of groups consisting of an isoxazolinyl group, an isoxazolidinyl group, a tetrahy-
dropyridyl group, an imidazolidinyl group, a tetrahydrofuranyl group, a piperazinyl group, a piperidinyl group,
a pyrrolidinyl group, pyrrolinyl group, a morpholino group, a tetrahydroquinolinyl group and a tetrahydroiso-
quinolinyl group, all of which may be substituted with one to three of said substituent(s); W 2 is a single bond,
an oxygen atom, a sulfur atom, SO, S0 2 , NR t , S0 2 NR t , N(R t )S0 2 NR u , N(R t )S0 2 , CH(OR t ), CONR t , N(R t )CO,
N(R t )CONR u , N(R t )COO, N(R t )CSO, N(R t )COS, C(R v )=CR r , C^C, CO, CS, OC(O), OC(0)NR t , OC(S)NR t ,
SC(O), SC(0)NR t and C(0)0 (wherein: R t and R u are each a hydrogen atom or a substituent selected from
a set of groups consisting of a lower alkyl group, a hydroxy group, a cyano group, halogen atoms, a nitro
group, a carboxyl group, a carbamoyl group, a formyl group, a lower alkanoyl group, a lower alkanoyloxy
group, a hydroxy lower alkyl group, a cyano lower alkyl group, a halo lower alkyl group, a carboxy lower alkyl
group, a carbamoyl lower alkyl group, lower alkoxy group, a lower alkoxycarbonyl group, lower alkoxycarbo-
nylamino group, a lower alkoxycarbonylamino lower alkyl group, a lower alkylcarbamoyl group, a di-lower
alkylcarbamoyl group, a carbamoyloxy group, a lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy
group, an amino group, a lower alkylamino group, a di-lower alkylamino group, a tri-lower alkylammonio group,
an amino lower alkyl group, a lower alkylamino lower alkyl group, a di-lower alkylamino lower alkyl group, a
tri-lower alkylammonio lower alkyl group, a lower alkanoylamino group, an aroylamino group, a lower alkanoy-
lamidino lower alkyl group, a lower alkylsulf inyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino
group, a hydroxyimino group and a lower alkoxyimino group, or a lower alkyl group, an aryl group or an aralkyl
group which may be substituted with one to three of said substituent or substituents); Y 3 and Y 4 are each, the
same or different, a single bond or a straight-chain or branched lower alkylene group, or R-| is an lower alkyl
group which may be substituted with one to three of the same or different substituent or substituents selected
from a set of groups consisting of a lower alkyl group, a hydroxyl group, a cyano group, halogen atoms, a nitro
group, a carboxyl group, a carbamoyl group, a formyl group, a lower alkanoyl group, a lower alkanoyloxy
group, a hydroxy lower alkyl group, a cyano lower alkyl group, a halo lower alkyl group, a carboxy lower alkyl
group, a carbamoyl lower alkyl group, lower alkoxy group, a lower alkoxycarbonyl group, lower alkoxycarbo-
nylamino group, a lower alkoxycarbonylamino lower alkyl group, a lower alkylcarbamoyl group, a di-lower
alkylcarbamoyl group, a carbamoyloxy group, a lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy
group, an amino group, a lower alkylamino group, a di-lower alkylamino group, a tri-lower alkylammonio group,
an amino lower alkyl group, a lower alkylamino lower alkyl group, a di-lower alkylamino lower alkyl group, a
tri-lower alkylammonio lower alkyl group, a lower alkanoylamino group, an aroylamino group, a lower alkanoy-
lamidino lower alkyl group, a lower alkylsulf inyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino
group, a hydroxyimino group and a lower alkoxyimino group, and a substituent selected from groups repre-
sented by the formula Y 3 -W 2 -Y 4 -R s (wherein: R s , W 2 , Y 3 and Y 4 have the same meanings as stated above),
or R 1 forms a nitrogen atom together with X; R 2 and R 3 are each independently, the same or different, a
hydrogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, or a substituent represented by
the formula Y 3 -W 2 -Y 4 -R s (wherein: R s . W 2 , Y 3 and Y 4 have the same meanings as stated above), or either
one of R 2 or R 3 forms, together with R 1 and X, a saturated five- to eight-membered cyclic group selected from
sets of groups of (a) and (b):

266

EP 1 199 306 A1

and

^ ^ <-\ N A

and

and the other one of R 2 or R 3 binds to a carbon atom or a nitrogen atom on the ring, or to a carbon atom, an
oxygen atom and/or nitrogen atom on said ring-substituent to form a five- to seven -mem be red ring, or R 2 and
R 3 are combined to form a spiro cyclo lower alkyl group, or R 2 and R 3 are conbined furthermore with Z on
which they exist to form an oxo (keto, or carbonyl) group, or they (R 2 and R 3 ) form, together with Z, R 1 and X
on which they stand, a saturated or an unsaturated five- to eight-membered cyclic group which may be selected
from sets of groups of (a) and (b):

00

o o o o o

o o O O

and

and

.N. . s q m

o • o . o • (!) ■ 0

N -J • 1/ ■ O and O

which may contain one or .more kinds of hetero atom(s) selected from a group of a nitrogen atom, an oxygen
atom and a sulfur atom, or which may be fused with any of a cyclo lower alkyl group, an aryl group, a heter-
oaromatic ring group selected from a set of groups consisting of an imidazolyl group, an isoxazolyl group, an
isoquinolyl group, an isoindolyl group, an indazolyl group, an indolyl group, an indolydinyl group, an isothiazolyl
group, an ethylenedioxyphenyl group, an oxazolyl group, a pyridyl group, a pyradinyl group, a pyrimidinyl
group, a pyridazinyl group, a pyrazolyl group, a quinoxalinyl group, a quinolyl group, a dihydroisoindolyl group,
a dihydroindolyl group, athionaphthenyl group, a naphthyridinyl group, a phenazinyl group, a benzoimidazolyl
group, a benzoxazolyl group, a benzothiazolyl group, a benzotriazolyl group, a benzofuranyl group, a thiazolyl
group, a thiadiazolyl group, a thienyl group, a pyrrolyl group, afuryl group, afurazanyl group, atriazolyl group,
a benzodioxanyl group and a methylenedioxyphenyl group, or an aliphatic heterocyclic group(s) selected from
a set of groups consisting of an isoxazolinyl group, an isoxazolidinyl group, a tetrahydropyridyl group, an
imidazolidinyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a piperazinyl group, a piperidinyl
group, a pyrrolidinyl group, pyrrolinyl group, a morpholino group, a tetrahydroquinolinyl group and a tetrahy-
droisoquinolinyl group, which may be substituted with one to three of the same or different substituent(s)
selected from a set of groups consisting of a lower alkyl group, a spiro cyclo lower alkyl group which may be
substituted, a hydroxyl group, a cyano group, halogen atoms, a nitro group, a carboxyl group, a carbamoyl
group, aformyl group, a lower alkanoyl group, a lower alkanoyloxy group, a hydroxy lower alkyl group, a cyano
lower alkyl group, a halo lower alkyl group, a carboxy lower alkyl group, a carbamoyl lower alkyl group, lower
alkoxy group, a lower alkoxycarbonyl group, lower alkoxycarbonylamino group, a lower alkoxycarbonylamino
lower alkyl group, a lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group, a carbamoyloxy group, a

267

EP 1 199 306 A1

lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy group, an amino group, a lower alkylamino group,
a di-lower alkylamino group, a tri-lower alkylammonio group, an amino lower alkyl group, a lower alkylamino
lower alkyl group, a di-lower alkylamino lower alkyl group, a tri-lower alkylammonio lower alkyl group, a lower
alkanoylamino group, an aroylamino group, a lower alkanoylamidino lower alkyl group, a lower alkylsulfinyl
group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a hydroxyimino group and a lower alkox-
yimino group, and a substituent selected from groups represented by the formula Y^W^Yg-Rp (wherein: R p ,
W-|, Y-| and Y 2 have the same meanings as stated above); R 4 and R 5 are each, the same or different, a
hydrogen atom, halogen atoms, a hydroxy group, an amino group, or a substituent represented by the formula
Y 3 -W 2 -Y 4 -R s (wherein: R s , W 2 , Y 3 and Y 4 have the same meanings as stated above), or any of a lower alkyl
group, an aryl group or an aralkyl group which may be substituted with one to three of the same of different
substituent or substituents selected from both a set of groups consisting of a lower alkyl group, a cyano group,
a nitro group, a carboxyl group, a carbamoyl group, a formyl group, a lower alkanoyl group, a lower alkanoyloxy
group, a hydroxy lower alkyl group, a cyano lower alkyl group, a halo lower alkyl group, a carboxy lower alkyl
group, a carbamoyl lower alkyl group, lower alkoxy group, a lower alkoxycarbonyl group, lower alkoxycarbo-
nylamino group, a lower alkoxycarbonylamino lower alkyl group, a lower alkylcarbamoyl group, a di-lower
alkylcarbamoyl group, a carbamoyloxy group, a lower alkylcarbamoyloxy group, di-lower alkylcarbamoyloxy
group, an amino group, a lower alkylamino group, a di-lower alkylamino group, a tri-lower alkylammonio group,
an amino lower alkyl group, a lower alkylamino lower alkyl group, a di-lower alkylamino lower alkyl group, a
tri-lower alkylammonio lower alkyl group, a lower alkanoylamino group, an aroylamino group, a lower alkanoy-
lamidino lower alkyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino
group, a hydroxyimino group and a lower alkoxyimino group, or groups represented by the formula Y 3 -W 2 -Y 4 -
R s (wherein: R s , W 2 , Y 3 and Y 4 have the same meanings as stated above); and the formula ~ represents
either a single bond or a double bond.

268

EP 1 199 306 A1

INTERNATIONAL SEARCH REPORT

International application No.

PCT/JP00/04991

A. CLASSIFICATION OF SUBJECT MATTER

Int. CI 7 C07D213/75, 81, 239/42, 47, 241/20, 40, 277/48, 32, 487/04, 519/00,
498/04, 409/12, 417/12, 401/10, A61K31/4402, 44, 4439, 505, 50, 415, 426 r 428,
553, 5383, 4545, 4436\ 4155, A61P43/00, 35/00,

According to International Patent Classification (IPC) or to both national classification and IPC

B. FIELDS SEARCHED

Minimum documentation searched (classification system followed by classification symbols)

Int. CI 7 C07D213/00-81, 239/00-47, 241/00-40, 277/00-82, 487/00-04, 519/00,
498/00-04, 409/00-12, 417/00-12, 401/00-10, A61K31/00-553

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched

Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)
REGISTRY ( STN) , CAPLUS { STN)

C. DOCUMENTS CONSIDERED TO BE RELEVANT

Category*

Citation of document, with indication, where appropriate, of the relevant passages

Relevant to claim No.

PX
PY
PA

WO, 00/26203, Al (PHARMACIA & UPJOHN S.P.A.),
11 May, 2000 (11.05.00),

Claims; pages 30-31; page 62, lines 3 to 4 ; page 66, lines
25 to 26, etc. (Family; none)

1,2,4,
7,8,
10

PX
PY
PA

WO, 99/65884, Al (BRISTOL-MYERS SQUIBB COMPANY) ,
23 December, 1999 (23.12.99),
Claims; full text
( Fami ly : none >

1,2
7,8
10

PX
PY

WO, 00/475 77, Al (SMITHKLINE BEECHAM PLC) ,
17 August, 2000 (17.08.00),
specification, page 27 r example 23
(Family: none)

1
7,8

X
Y

WO, 99/31086, Al (SMITHKLINE BEECHAM PLC) ,
24 June, 1999 (24.06.99),
specification, page 46, example 68
& EP, 1047691, Al

1
7, 8

A

WO, 99/24416, Al (BRISTOL-MYERS SQUIBB COMPANY) ,
20 May, 1999 (20.05.99),

1-10

Further documents are listed in the continuation ofBox C.

| | See paten t fami ly annex .

* Special categories of cited documents:

"A" document defining the general state of the art which is not

considered to be of particular relevance
*E* earlier document but published on or after the international filing

date

"L* document which may throw doubts on priority clnim(s) or which is
cited to establish the publication date of another citation or other
special reason (as specified)

"0" document referring to an oral disclosure, use, exhibition or other
means

"P" document published prior to the international filing date but later
than the priority date claimed

'T* later document published after the intemational filing date or
priority date and not in conflict with the application but cited to
understand the principle or theory underlying the invention

"X" document of particular relevance; the claimed invention cannot be
considered novel or cannot be considered to involve an inventive
step when the document is taken alone

"Y" document of particular relevance; the claimed invention cannot be
considered to involve an inventive step when the document is
combined with one or more other such documents, such
combination being obvious to a person skilled in the art

"8c" document member of the same patent family

Date of the actual completion of the international search
17 November, 2000 (17.11.00)

Date of mailing of the international search report

28 November, 2000 (28.11.00)

Name and mailing address of the ISA/

Japanese Patent Office

Authorized officer

Facsimile No.

Telephone No.

Form PCT/ISA/210 (second sheet) (July 1992)

269

EP 1 199 306 A1

INTERNATIONAL SEARCH REPORT

International application No.

PCT/JPOO/04991

C (Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT

Category*

Citation of document, with indication, where appropriate, of the relevant passages

Relevant to claim No.

Y
A

Pull text

& US, 6040321, A & AU f 9912955, Al
& BR, 9814124, A & EP, 1042307, Al

MARCH, J. , "Advanced Organic Chemistry, Third Edition"
John Wiley & Sons, p. 786, 964-985 (1985)

PINES, J.

The cell cycle kinases .

Semin. Cancer Biol., Vol.5, No. 4, p. 305-313 (1994)

7,8
10

Form PCT/ISA/210 (cowfmnAtion of second sheet) (July 1992)

270